Biphenyl compounds useful as muscarinic receptor antagonists

ABSTRACT

The invention provides compounds of formula I: 
                         
wherein a, b, c, m, s, t, W, Z, Ar, R 1 , R 2 , R 3 , R 6 , and R 7  are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/690,008, filed on Jun. 13, 2005; the disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel biphenyl compounds havingmuscarinic receptor antagonist or anticholinergic activity. Theinvention also relates to pharmaceutical compositions comprising thesecompounds, processes and intermediates for preparing these compounds andmethods of using these compounds to treat pulmonary disorders.

2. State of the Art

Pulmonary or respiratory disorders, such as chronic obstructivepulmonary disease (COPD) and asthma, afflict many millions of peopleworldwide and are a leading cause of morbidity and mortality. Muscarinicreceptor antagonists are known to provide bronchoprotective effects andtherefore are useful for treating respiratory disorders, such as COPDand asthma. Muscarinic receptor antagonists are typically administeredby inhalation to treat these disorders. However, even when administeredby inhalation, a significant amount of the antagonist is often absorbedinto the systemic circulation resulting in systemic side effects, suchas dry mouth, mydriasis and cardiovascular side effects. In addition,many inhaled muscarinic receptor antagonists have a relatively shortduration of action requiring that they be administered several times perday. This multiple-daily dosing regime is inconvenient and creates asignificant risk of inadequate treatment due to patient non-compliancewith the required frequent dosing schedule.

Accordingly, a need exists for new muscarinic receptor antagonists, inparticular, those having high potency and reduced systemic side effectswhen administered by inhalation. Additionally, a need exists for inhaledmuscarinic receptor antagonists having a long duration of action therebyallowing for once-daily or even once-weekly dosing. Such compounds areexpected to be particularly effective for treating pulmonary disorders,such as COPD and asthma, while reducing or eliminating side effects,such as dry-mouth and constipation.

SUMMARY OF THE INVENTION

The present invention provides novel biphenyl compounds havingmuscarinic receptor antagonist or anticholinergic activity. Among otherproperties, compounds of the invention are expected to possess highpotency and reduced systemic side effects when administered byinhalation and are also expected to possess a long duration of action.

One aspect of the invention relates to a compound of formula I:

wherein:

a is 0 or an integer of from 1 to 5;

each R¹ is independently selected from —C₁₋₅alkyl, —C₂₋₅alkenyl,—C₂₋₅alkynyl, —C₃₋₆cycloalkyl, -cyano, -halo, —OR^(1a), —C(O)OR^(1b),—SR^(1c), —S(O)R^(1d), S(O)₂R^(1e), —NR^(1f)R^(1g), —NR^(1h)S(O)₂R^(1i),and —NR^(1j)C(O)R^(1k); where each of R^(1a-1k) is independently —H,—C₁₋₅alkyl or -phenyl-C₁₋₅alkyl;

b is 0 or an integer of from 1 to 4;

each R² is independently selected from —C₁₋₅alkyl, —C₂₋₅alkenyl,—C₂₋₅alkynyl, —C₃₋₆cycloalkyl, -cyano, -halo, —OR^(2a), —C(O)OR^(2b),SR^(2c), —S(O)R^(2d), S(O)₂R^(2e), NR^(2f)R^(2g), —NR^(2h)S(O)₂R^(2i),and —NR^(2j)C(O)R^(2k); where each of R^(2a-2k) is independently —H,—C₁₋₅alkyl or -phenyl-C₁₋₅alkyl;

W is —O— or —NW^(a)—, where W^(a) is —H or —C₁₋₅alkyl;

c is 0 or an integer from 1 to 5;

each R³ independently is —C₁₋₅alkyl or two R³ groups are joined to formC₁₋₃alkylene, C₂₋₃alkenylene or oxiran-2,3-diyl;

m is 0 or 1;

Z is selected from —C(O)N(R⁴)— and —N(R⁴)C(O)—, where R⁴ is selectedfrom —H, —C₁₋₅alkyl, and —C₃₋₅cycloalkyl;

s is 0, 1 or 2;

Ar is a phenylene group or a C₃₋₅heteroarylene group containing 1 or 2heteroatoms independently selected from oxygen, nitrogen or sulfur;wherein the phenylene or C₃₋₅heteroarylene group is substituted with(R⁵)_(q) where q is 0 or an integer from 1 to 4 and each R⁵ isindependently selected from -halo, —OH, —C₁₋₅alkyl or —C₁₋₅alkoxy;

t is 0, 1 or 2;

R⁶ is selected from —H, —C₁₋₅alkyl, and —X⁶R^(6a); where X⁶ is—C₁₋₅alkylene and R^(6a) is selected from —OH, —C₁₋₅alkoxy and-heteroaryl; and

R⁷ is selected from —H, —C₁₋₅alkyl, —C₃₋₆cycloalkyl, and —X⁷R^(7a);where X⁷ is selected from —C₁₋₅alkylene, —C(O)—, —C₁₋₅alkylene-C(O)—,—S(O₂)—, —C₁₋₅alkylene-S(O₂)—, and —S(O₂)—C₁₋₅alkylene; and R^(7a) isselected from —OH, —C₁₋₅alkyl, —C₃₋₆cycloalkyl, —C₁₋₅alkoxy, heteroaryl,—NR^(7b)R^(7c), where R^(7b) and R^(7c) are independently —H or—C₁₋₅alkyl, and aryl optionally substituted with 1-2-C₁₋₅alkyl or halogroups;

or R⁶ and R⁷ are taken together to form:

optionally substituted with one to three —C₁₋₅alkyl groups, or

where: d is 1 or 2; e is 0, 1 or 2; f is 0, 1, 2 or 3; R⁸ is selectedfrom —C₁₋₅alkyl and ═O; R⁹ is selected from —H, —C₁₋₅alkyl,hydroxyphenyl, heteroaryl, and —X⁹R^(9a); where X⁹ is selected from—C₁₋₅alkylene, —C(O)—, —C₁₋₅alkylene-C(O)—, —C(O)—C₁₋₅alkylene, —S(O₂)—,—C₁₋₅alkylene-S(O₂)—, and —S(O₂)—C₁₋₅alkylene; and R^(9a) is selectedfrom —H, —OH, —C₁₋₅alkyl, —C₁₋₅alkoxy, aryl, heteroaryl, heterocyclyl,and —NR^(9b)R^(9c), where R^(9b) and R^(9c) are independently —H or—C₁₋₅alkyl;

wherein each alkyl and alkoxy group in R¹, R^(1a-1k), R², R^(2a-2k), R³,R⁵, R⁶, R^(6a), R⁷, R^(7a-c), R⁸, R⁹, and R^(9a-c) is optionallysubstituted with 1 to 5 fluoro substituents;

or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

Another aspect of the invention pertains to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof. Yet another aspect ofthe invention pertains to compositions comprising a compound of formulaI in combination with one or more other therapeutic agents. Accordingly,in one embodiment, the invention is directed to compositions comprising(a) a pharmaceutically acceptable carrier and a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt or solvate or stereoisomer thereof; and (b) atherapeutically effective amount of an agent selected from a steroidalanti-inflammatory agent such as a corticosteroid; a β₂ adrenergicreceptor agonist; a phosphodiesterase-4 inhibitor; or a combinationthereof; wherein the compound of formula I and the agent are formulatedtogether or separately. When the agent is formulated separately, apharmaceutically acceptable carrier may be included.

Compounds of the invention possess muscarinic receptor antagonistactivity. Accordingly, compounds of formula I are expected to be usefulfor treating pulmonary disorders, such as chronic obstructive pulmonarydisease and asthma.

Yet another aspect of the invention is directed to methods for treatinga pulmonary disorders comprising administering to a patient atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt or solvate or stereoisomer thereof.Still another aspect of the invention pertains to methods of producingbronchodilation in a patient comprising administering to a patient abronchodilation-producing amount of a compound of formula I or apharmaceutically acceptable salt or solvate or stereoisomer thereof. Theinvention is also directed to methods of treating chronic obstructivepulmonary disease or asthma comprising administering to a patient atherapeutically effective amount of a compound of formula I or apharmaceutically acceptable salt or solvate or stereoisomer thereof. Inanother aspect, the invention is directed to methods for antagonizing amuscarinic receptor in a mammal comprising administering to the mammal atherapeutically effective amount of the compound of formula I.

Since compounds of the invention possess muscarinic receptor antagonistactivity, such compounds are also useful as research tools. Accordingly,in yet another embodiment, the invention is directed to methods forusing a compound of formula I or a pharmaceutically acceptable salt orsolvate or stereoisomer thereof as a research tool for studying abiological system or sample, or for discovering new chemical compoundshaving muscarinic receptor antagonist activity.

The invention is also directed to processes and intermediates useful forpreparing compounds of formula I and pharmaceutically acceptable saltsor solvates or stereoisomers thereof. Accordingly, in anotherembodiment, the invention is directed to a process of preparing acompound of formula I, the process comprising: (a) reacting a compoundof formula II with a compound of formula III; or (b) coupling a compoundof formula IVa with a compound of formula Va or coupling a compound offormula IVb with a compound of formula Vb; or (c) reacting a compound offormula VI with a compound of formula VII; or (d) reacting a compound offormula II with a compound of formula VIII in the presence of a reducingagent; or (e) reacting a compound of formula IX with a compound offormula VII in the presence of a reducing agent; and then removing anyprotecting groups that may be present to provide a compound of formulaI, and optionally, forming a pharmaceutically acceptable salt thereof,wherein compounds of formula I-IX, are as defined herein.

In one embodiment, the above process further comprises the step offorming a pharmaceutically acceptable salt of a compound of formula I.In other embodiments, the invention is directed to the other processesdescribed herein; and to the products prepared by any of the processesdescribed herein.

The invention is also directed to a compound of formula I or apharmaceutically acceptable salt or solvate or stereoisomer thereof, foruse in therapy or as a medicament. Additionally, the invention isdirected to the use of a compound of formula I or a pharmaceuticallyacceptable salt or solvate or stereoisomer thereof, for the manufactureof a medicament; especially for the manufacture of a medicament for thetreatment of a pulmonary disorder or for antagonizing a muscarinicreceptor in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the invention is directed to novel biphenyl compoundsof formula I, and pharmaceutically acceptable salts or solvates orstereoisomers thereof. The compounds may contain one or more chiralcenters and therefore, the invention is also directed to racemicmixtures, pure stereoisomers (i.e., enantiomers or diastereomers),stereoisomer-enriched mixtures, and the like unless otherwise indicated.When a particular stereoisomer is shown or named herein, it will beunderstood by those skilled in the art that minor amounts of otherstereoisomers may be present in the compositions of the invention unlessotherwise indicated, provided that the desired utility of thecomposition as a whole is not eliminated by the presence of such otherisomers.

The compounds of formula I also contain several basic groups (e.g.,amino groups) and therefore, the compounds of formula I can exist as thefree base or in various salt forms. All such salt forms are includedwithin the scope of the invention. Furthermore, solvates of compounds offormula I or salts thereof are included within the scope of theinvention. Additionally, where applicable, all cis-trans or E/Z isomers(geometric isomers), tautomeric forms and topoisomeric forms of thecompounds of formula I are included within the scope of the inventionunless otherwise specified.

The compounds of formula I, as well as those compounds used in itssynthesis, may also include isotopically-labeled compounds, i.e., whereone or more atoms have been enriched with atoms having an atomic massdifferent from the atomic mass predominately found in nature. Examplesof isotopes that may be incorporated into the compounds of formula Iinclude, but are not limited to, ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O and ¹⁷O.

The nomenclature used herein to name the compounds of the invention isillustrated in the Examples. This nomenclature has been derived usingthe commercially-available AutoNom software (MDL, San Leandro, Calif.).For example, compounds of formula I wherein W is O have typically beennamed as ester derivatives of biphenyl-2-ylcarbamic acid.

Representative Embodiments

The following substituents and values are intended to providerepresentative examples of various aspects and embodiments of theinvention. These representative values are intended to further defineand illustrate such aspects and embodiments and are not intended toexclude other embodiments or to limit the scope of the invention. Inthis regard, the representation that a particular value or substituentis preferred is not intended in any way to exclude other values orsubstituents from the invention unless specifically indicated.

The value for a is 0, 1, 2, 3, 4 or 5; particularly 0, 1 or 2, and evenmore particularly 0 or 1. The value for b is 0, 1, 2, 3 or 4;particularly 0, 1 or 2, and even more particularly 0 or 1. In oneembodiment, both a and b are 0. When present, each R¹ may be at the 2,3, 4, 5 or 6-position of the phenyl ring to which it is attached. EachR¹ is independently selected from —C₁₋₅alkyl, —C₂₋₅alkenyl,—C₂₋₅alkynyl, —C₃₋₆cycloalkyl, -cyano, -halo, —OR^(1a), —C(O)OR^(1b),—SR^(1c), —S(O)R^(1d), —S(O)₂R^(2e), —NR^(2f)R^(2g),—NR^(2h)S(O)₂R^(1i), and —NR^(1j)C(O)R^(1k), examples of which includemethyl, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino,dimethylamino and the like. Particular values for R¹ are fluoro orchloro. When present, each R² may be at the 3, 4, 5 or 6-position on thephenylene ring to which it is attached (where the carbon atom on thephenylene ring attached to the nitrogen atom is position 1). Each R² isindependently selected from —C₁₋₅alkyl, —C₂₋₅alkenyl, —C₂₋₅alkynyl,—C₃₋₆cycloalkyl, -cyano, -halo, —OR^(2a), —C(O)OR^(2b), —SR^(2c),—S(O)R^(2d), —S(O)₂R^(2e), —NR^(2f)R^(2g), —NR^(2h)S(O)₂R^(2i), and—NR^(2j)C(O)R^(2k), examples of which include methyl, fluoro, chloro,bromo, hydroxy, methoxy, amino, methylamino, dimethylamino and the like.Particular values for R² are fluoro or chloro.

Each R^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g), R^(1h),R^(1i), R^(1j), and R^(1k) and R^(2a), R^(2b), R^(2c), R^(2d), R^(2e),R^(2f), R^(2g), R^(2h), R^(2i), R^(1j), and R^(2k) as used in R¹ and R²,respectively, is independently —H, —C₁₋₅alkyl or -phenyl-C₁₋₅alkyl,examples of which include hydrogen, methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, isobutyl, tert-butyl or benzyl. In one embodiment,these groups are independently hydrogen or —C₁₋₃alkyl. In anotherembodiment, these groups are independently hydrogen, methyl or ethyl. Inaddition, each alkyl and alkoxy group in R¹, R^(1a-1k), R², andR^(2a-2k) is optionally substituted with 1 to 5 fluoro substituents.

In one embodiment of the invention, W is —O—. Generally, it has beenfound that compounds in which W represents —O— exhibit particularly highaffinity for muscarinic receptors. In another embodiment W is —NW^(a)—,where W^(a) is —H or —C₁₋₄alkyl, examples of which include hydrogen,methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl andtert-butyl. In one embodiment, W^(a) is hydrogen or —C₁₋₃alkyl. Inanother embodiment, W^(a) is hydrogen, methyl or ethyl, particularlyhydrogen or methyl. In yet another embodiment, W^(a) is hydrogen and—NW^(a)— is —NH—.

The value for c is 0, 1, 2, 3, 4, or 5; particularly 0, 1, or 2; andmore particularly 0 or 1. In one particular embodiment, c is 0. Each R³independently represents —C₁₋₅alkyl or two R³ groups that are joined toform C₁₋₃alkylene, C₂₋₃alkenylene or oxiran-2,3-diyl. In one embodiment,each R³ is independently —C₁₋₅alkyl, such as methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In addition,each alkyl group in R³ is optionally substituted with 1 to 5 fluorosubstituents. In one embodiment, each R³ is independently —C₁₋₃alkyl,and in another embodiment, each R³ is independently methyl or ethyl.

In one embodiment, each R³ is at the 3, 4 or 5-position on thepiperidine ring (where the nitrogen atom of the piperidine ring isposition 1). In a particular embodiment, R³ is at the 4-position on thepiperidine ring. In another embodiment, R³ is at the 1-position of thepiperidine ring, i.e., on the nitrogen atom of the piperidine ring thusforming a quaternary amine salt.

In yet another embodiment, two R³ groups are joined to form aC₁₋₃alkylene or C₂₋₃alkenylene group. For example, two R³ groups at the2 and 6-positions on the piperidine ring can be joined to form anethylene bridge (i.e., the piperidine ring and the R³ groups form an8-azabicyclo[3.2.1]octane ring); or two R³ groups at the 1 and4-positions on the piperidine ring can be joined to form an ethylenebridge (i.e., the piperidine ring and the R³ groups form an1-azabicyclo[2.2.2]octane ring). In this embodiment, other R³ groups asdefined herein may also be present.

In still another embodiment, two R³ groups are joined to form aoxiran-2,3-diyl group. For example, two R³ groups at the 2 and6-positions on the piperidine ring can be joined to form a3-oxatricyclo[3.3.1.0^(2,4)]nonane ring). In this embodiment, other R³groups as defined herein may also be present.

The value for m is 0 or 1. In one embodiment, m is 0.

Z is selected from —C(O)N(R⁴)— and —N(R⁴)C(O)—. R⁴ is —H, —C₁₋₅alkyl, or—C₃₋₅cycloalkyl. Examples of —C₁₋₅alkyl groups include methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, andpentyl. Examples of —C₃₋₅cycloalkyl groups include cyclopropyl,cyclobutyl, and cyclopentyl. In one embodiment R⁴ is hydrogen or—C₁₋₃alkyl, in particular hydrogen or methyl. Exemplary embodiments of Zinclude —NHC(O)—, —N(CH₃)C(O)—, and —C(O)NH—.

The value for s is 0, 1 or 2. One particular value for s is 0; inanother embodiment, s is 1; and in yet another embodiment, the value fors is 2.

Ar is a phenylene group or a C₃₋₅heteroarylene group containing 1 or 2heteroatoms independently selected from oxygen, nitrogen or sulfur. Thephenylene or heteroarylene group may be unsubstituted (q is 0) orsubstituted with 1, 2, 3, or 4 (q is 1, 2, 3, or 4) R⁵ substituents,which are independently selected from -halo, —OH, —C₁₋₅alkyl or—C₁₋₅alkoxy. In addition, each alkyl and alkoxy group in R⁵ isoptionally substituted with 1 to 5 fluoro substituents. In oneembodiment, q is 0, 1, 2 or 3; in another embodiment, q is 0, 1 or 2. Inanother embodiment, q is 1 and R⁵ is methoxy. The point of attachmentfor Ar is at any available carbon or heteroatom ring atom. In certainembodiments, Ar is a phenylene group attached at the meta or paraposition.

In one embodiment Ar is phen-1,3-ylene or phen-1,4-ylene wherein thephenylene group is unsubstituted or substituted with 1, 2 or 3 R⁵substituents. Representative R⁵ substituents include fluoro, chloro,bromo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,tert-butyl, methoxy, ethoxy, isopropoxy, difluoromethyl,trifluoromethyl, 2,2,2-trifluoroethyl and trifluoromethoxy. Particularexamples of Ar¹ groups in this embodiment include2-fluorophen-1,4-ylene, 3-fluorophen-1,4-ylene, 2-chlorophen-1,4-ylene,3-chlorophen-1,4-ylene, 2-methylphen-1,4-ylene, 3-methylphen-1,4-ylene,2-methoxyphen-1,4-ylene, 3-methoxyphen-1,4-ylene,2-trifluoromethoxyphen-1,4-ylene, 3-trifluoromethoxyphen-1,4-ylene,2,3-difluorophen-1,4-ylene, 2,5-difluorophen-1,4-ylene,2,6-difluorophen-1,4-ylene, 2,3-dichlorophen-1,4-ylene,2,5-dichlorophen-1,4-ylene, 2,6-dichlorophen-1,4-ylene,2-chloro-5-methoxyphen-1,4-ylene, 2-chloro-6-methoxyphen-1,4-ylene,2-chloro-5-trifluoromethoxyphen-1,4-ylene,2-chloro-6-trifluoromethoxyphen-1,4-ylene, and2,5-dibromophen-1,4-ylene.

In another embodiment, Ar is a C₃₋₅heteroarylene group containing 1 or 2heteroatoms, and is unsubstituted or substituted with 1 or 2 R⁵substituents. Representative C₃₋₅heteroarylene groups include divalentspecies of pyrrole, imidazole, thiazole, oxazole, furan, thiophene,pyrazole, isoxazole, isothiazole; pyridine, pyrazine, pyridazine andpyrimidine, where the point of attachment is at any available carbon ornitrogen ring atom. More specific examples of such Ar groups include:pyridylene such as 2,5-pyridylene and 2,6-pyridylene; thienylene such as2,4-thienylene and 2,5-thienylene; pyrrolylene such as 2,4-pyrrolyleneand 2,5-pyrrolylene; and furylene such as 2,5-furylene. RepresentativeR⁵ substituents include fluoro, chloro, methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy,isopropoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl andtrifluoromethoxy. Particular examples of substituted Ar groups include3-fluoro-2,5-thienylene, 3-chloro-2,5-thienylene,3-methyl-2,5-thienylene, 3-methoxy-2,5-thienylene, and3-methoxy-6-chloro-2,5-pyridylene.

In one particular embodiment, Ar represents phen-1,3-ylene,phen-1,4-ylene, 2-methoxyphen-1,4-ylene, 2,5-pyridylene, 2,5-thienylene,2,4-pyrrolylene, 2,5-pyrrolylene, or 2,5-furylene.

The value for t is 0, 1 or 2. A particular value for t is 1.

R⁶ is selected from —H, —C₁₋₅alkyl, and —X⁶R^(6a), where X⁶ is—C₁₋₅alkylene and R^(6a) is selected from —OH, —C₁₋₅alkoxy and-heteroaryl. In one embodiment, R⁶ is —H. In another embodiment, R⁶ is—C₁₋₅alkyl such as methyl or ethyl. In another embodiment, R⁶ is—X⁶R^(6a), where X⁶ is —C₁₋₅alkylene such as —(CH₂)₂—, and R^(6a) is—OH. In yet another embodiment, R⁶ is —X⁶R^(6a), where X⁶ is—C₁₋₅alkylene such as —(CH₂)₂—, and R^(6a) is —C₁₋₅alkoxy such as —OCH₃or —OCH₂CH₃. In addition, each alkyl and alkoxy group in R⁶ and R^(6a)is optionally substituted with 1 to 5 fluoro substituents.

R⁷ is selected from —H, —C₁₋₅alkyl, —C₃₋₆cycloalkyl, and —X⁷R^(7a). X⁷is selected from —C₁₋₅alkylene, —C(O)—, —C₁₋₅alkylene-C(O)—, —S(O₂)—,—C₁₋₅alkylene-S(O₂)—, and —S(O₂)—C₁₋₅alkylene. R^(7a) is selected from—OH, —C₁₋₅alkyl, —C₃₋₆cycloalkyl, —C₁₋₅alkoxy, heteroaryl,—NR^(7b)R^(7c) (R^(7b) and R^(7c) are independently —H or —C₁₋₅alkyl),and aryl (which may be substituted with 1 or 2-C₁₋₅alkyl or halogroups). In addition, each alkyl and alkoxy group in R⁷ and R^(7a-c) isoptionally substituted with 1 to 5 fluoro substituents. For example, R⁷can be —CH₂CH₂CF₃ or —S(O₂)CF₃. In one embodiment, R⁷ is —H. In oneembodiment, R⁷ is —C₁₋₅alkyl such as methyl, ethyl, isopropyl, isobutyl,and tert-butyl. In another embodiment, R⁷ is —C₃₋₆cycloalkyl such ascyclopropyl, cyclobutyl, or cyclopentyl. In yet another embodiment, R⁷is —X⁷R^(7a), where X⁷ is —C₁₋₅alkylene such as —CH₂—, and R^(7a) is:—C₃₋₆cycloalkyl such as cyclopropyl; heteroaryl such as 2-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 5-benzo[1,3]dioxole, or7-1H-indole. X⁷ can also be —C₁₋₅alkylene such as —(CH₂)₂—, and R^(7a)can be —OH, or —C₁₋₅alkoxy such as —OCH₃ and —OCH₂CH₃. R⁷ can also be—X⁷R^(7a), where X⁷ is —C(O)—, and R^(7a) is —C₁₋₅alkyl such as methyl,—C₃₋₆cycloalkyl such as cyclopropyl or cyclobutyl, heteroaryl such as2-furyl, 2-thienyl, or 4-pyridyl. In another embodiment, R⁷ is—X⁷R^(7a), where X⁷ is —C₁₋₅alkylene-C(O)— such as —CH₂C(O)—, and R^(7a)is: —OH; or —NR^(7b)R^(7c) such as —NH₂. R⁷ can also be —X⁷R^(7a), whereX⁷ is —S(O₂)—, and R^(7a) is: —C₁₋₅alkyl such as methyl, ethyl,n-propyl, isopropyl, and n-butyl; heteroaryl such as 2-thienyl and8-quinolinyl; or aryl such as 4-trifluoromethylphenyl, 2-fluorophenyl,2,6-dichlorophenyl, 4-methylphenyl, and phenyl. In another embodiment,R⁷ is —X⁷R^(7a), where X⁷ is —C₁₋₅alkylene-S(O₂)— such as —(CH₂)₂S(O₂)—,and R^(7a) is —C₁₋₅alkyl such as methyl. In yet another embodiment, R⁷is —X⁷R^(7a), where X⁷ is —S(O₂)—C₁₋₅alkylene such as —S(O₂)(CH₂)₂—, andR^(7a) is —NR^(7b)R^(7c) such as —NHCH₃.

One particular R⁶/R⁷ combination is where R⁶ is —H and R⁷ is —H,—C₁₋₅alkyl (e.g., methyl, ethyl, isopropyl, isobutyl, or tert-butyl), or—C₃₋₆cycloalkyl (e.g., cyclopropyl, cyclobutyl, or cyclopentyl). Inanother combination, R⁶ is —H and R⁷ is —X⁷R^(7a), where X⁷ is—C₁₋₅alkylene (e.g., —CH₂—), and R^(7a) is —C₃₋₆cycloalkyl (e.g.,cyclopropyl) or heteroaryl (e.g., 2-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-furyl, 5-benzo[1,3]dioxole, or 7-1H-indole). X⁷ may also be—C₁₋₅alkylene such as —(CH₂)₂—, and R^(7a) is —OH or —C₁₋₅alkoxy such as—OCH₃. Another particular R⁶/R⁷ combination is where R⁶ is —H, and R⁷ is—X⁷R^(7a), where X⁷ is —C(O)—, and R^(7a) is: —C₁₋₅alkyl such as methyl;—C₃₋₆cycloalkyl such as cyclopropyl or cyclobutyl; or heteroaryl such as2-furyl, 2-thienyl, or 4-pyridyl.

Another particular R⁶/R⁷ combination is where R⁶ is —H, and R⁷ is—X⁷R^(7a), where X⁷ is —C₁₋₅alkylene-C(O)— such as —CH₂C(O)—, and R^(7a)is —NR^(7b)R^(7c) such as —NH₂. Another particular R⁶/R⁷ combination iswhere R⁶ is —H, and R⁷ is —X⁷R^(7a), where X⁷ is —S(O₂)—, and R^(7a) is—C₁₋₅alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, or n-butyl),heteroaryl (e.g., thiophen-2-yl or 8-quinolinyl), or aryl (e.g.,4-trifluoromethylphenyl, 2-fluorophenyl, 2,6-dichlorophenyl,4-methylphenyl, or phenyl). Another particular R⁶/R⁷ combination iswhere R⁶ is —H, and R⁷ is —X⁷R^(7a), where X⁷ is —S(O₂)—C₁₋₅alkylenesuch as —S(O₂)(CH₂)₂—, and R^(7a) is —NR^(7b)R^(7c) such as —NHCH₃.

Another particular R⁶/R⁷ combination is where R⁶ is —C₁₋₅alkyl such asmethyl, and R⁷ is: —X⁷R^(7a), where X⁷ is —C₁₋₅alkylene such as—(CH₂)₂—, and R^(7a) is —OH; —X⁷R^(7a), where X⁷ is —C₁₋₅alkylene suchas —CH₂—, and R^(7a) is heteroaryl such as 3-pyridyl, 4-pyridyl, or2-furyl; X⁷R^(7a), where X⁷ is —C₁₋₅alkylene-C(O)— such as —CH₂C(O)—,and R^(7a) is —OH; or X⁷R^(7a), where X⁷ is —C₁₋₅alkylene-S(O₂)— such as—(CH₂)₂S(O₂)—, and R^(7a) is —C₁₋₅alkyl such as methyl. Anotherparticular R⁶/R⁷ combination is where R⁶ and R⁷ are different —C₁₋₅alkylgroups. For example, R⁶ can be ethyl, and R⁷ can be methyl or isopropyl.

Another particular R⁶/R⁷ combination is where R⁶ and R⁷ are the same. R⁶and R⁷ can both be a —C₁₋₅alkyl group such as methyl and ethyl. R⁶ andR⁷ can also both be a —C₁₋₅alkylene-C₁₋₅alkoxy group (X⁶ and X⁷ are—C₁₋₅alkylene, R^(6a) and R^(7a) are —C₁₋₅alkoxy), examples of whichinclude —(CH₂)₂OCH₃ and —(CH₂)₂OCH₂CH₃. R⁶ and R⁷ can also both be a—C₁₋₅alkylene-OH group (X⁶ and X⁷ are —C₁₋₅alkylene, R^(6a) and R^(7a)are —OH), an example of which includes —(CH₂)₂OH.

Alternately, R⁶ and R⁷ may be taken together to form a thiomorpholine1,1-dioxide ring:

R⁶ and R⁷ may also be taken together to form morpholin-4-yl:

which may be substituted with one, two or three —C₁₋₅alkyl groups. Inone embodiment, the morpholine ring is substituted with two —C₁₋₅alkylgroups such as methyl, for example 2,6-dimethylmorpholin-4-yl. Inaddition, R⁶ and R⁷ may also be taken together to form:

The value for d is 1 or 2. In one embodiment, d is 1. The value for e is0, 1 or 2. In one embodiment, e is 0 and in another embodiment e is 1.In one embodiment, d is 1 and e is 0 or 1. The value for f is 0, 1, 2 or3. In one embodiment, f is 0. R⁸ is selected from —C₁₋₅alkyl and ═O. Inone embodiment, R⁸ is ═O. In addition, each alkyl group in R⁸ isoptionally substituted with 1 to 5 fluoro substituents.

R⁹ is selected from —H, —C₁₋₅alkyl, hydroxyphenyl, heteroaryl, and—X⁹R^(9a). X⁹ is selected from —C₁₋₅alkylene, —C(O)—,—C₁₋₅alkylene-C(O)—, —C(O)—C₁₋₅alkylene, —S(O₂)—, —C₁₋₅alkylene-S(O₂)—,and —S(O₂)—C₁₋₅alkylene. R^(9a) is selected from —H, —OH, —C₁₋₅alkyl,—C₁₋₅alkoxy, aryl, heteroaryl, heterocyclyl, and —NR^(9b)R^(9c) (R^(9b)and R^(9c) are independently —H or —C₁₋₅alkyl). In addition, each alkyland alkoxy group in R⁹ and R^(9a-c) is optionally substituted with 1 to5 fluoro substituents.

In one embodiment, R⁹ is —H or hydroxyphenyl. R⁹ can also be —C₁₋₅alkylsuch as ethyl and isopropyl. In another embodiment, R⁹ is heteroarylsuch as 4-pyridyl. In another embodiment, R⁹ is —X⁹R^(9a), where X⁹ is—C₁₋₅alkylene such as —CH₂—, and R^(9a) is heteroaryl such as 4-pyridyl,or where X⁹ is —C₁₋₅alkylene such as —(CH₂)₂—, and R^(9a) is —C₁₋₅alkoxysuch as —OCH₃. R⁹ can also be —X⁹R^(9a), where X⁹ is —C(O)—, and R^(9a)is: —H; —C₁₋₅alkyl such as methyl; —C₁₋₅alkoxy such as —OCH₃;heterocyclyl such as 1-pyrrolidinyl, 1-piperidyl, and 4-morpholinyl; or—NR^(9b)R^(9c) such as —N(CH₃)₂. In another embodiment, R⁹ is —X⁹R^(9a),where X⁹ is —C₁₋₅alkylene-C(O)— such as —CH₂C(O)—, and R^(9a) isheterocyclyl such as 1-pyrrolidinyl, or —NR^(9b)R^(9c) such as —N(CH₃)₂.R⁹ can also be —X⁹R^(9a), where X⁹ is —S(O₂)—, and R^(9a) is —C₁₋₅alkylsuch as methyl and ethyl.

In one embodiment, d is 1, e is 0, and f is 1, i.e., R⁶ and R⁷ are takentogether to form a piperidine ring. Particular embodiments of thepiperidine ring include those where R⁸ is ═O and R⁹ is —H, for example,a piperazin-2-one ring.

In one embodiment, d is 1, and e and f are 0, i.e., R⁶ and R⁷ are takentogether to form a piperidine ring. Particular embodiments of thepiperidine ring include those where R⁹ is: —C₁₋₅alkyl such as ethyl andisopropyl; hydroxyphenyl; heteroaryl such as 4-pyridyl; —X⁹R^(9a), whereX⁹ is —C₁₋₅alkylene such as —CH₂—, and R^(9a) is heteroaryl such as4-pyridyl; —X⁹R^(9a), where X⁹ is —C₁₋₅alkylene such as —(CH₂)₂—, andR^(9a) is —C₁₋₅alkoxy such as —OCH₃; —X⁹R^(9a), where X⁹ is —C(O)—, andR^(9a) is —H, —C₁₋₅alkyl such as methyl, —C₁₋₅alkoxy such as —OCH₃,heterocyclyl such as 1-pyrrolidinyl, 1-piperidyl, and 4-morpholinyl, or—NR^(9b)R^(9c) such as —N(CH₃)₂; —X⁹R^(9a), where X⁹ is—C₁₋₅alkylene-C(O)— such as —CH₂C(O)—, and R^(9a) is heterocyclyl suchas 1-pyrrolidinyl, or —NR^(9b)R^(9c) such as —N(CH₃)₂; and —X⁹R^(9a),where X⁹ is —S(O₂)—, and R^(9a) is —C₁₋₅alkyl such as methyl and ethyl.

In one embodiment, d is 2, and e and f are 0, i.e., R⁶ and R⁷ are takentogether to form a [1,4]diazepane ring. Particular embodiments of the[1,4]diazepane ring include those where R⁹ is —X⁹R^(9a), where X⁹ is—C(O)—, and R^(9a) is —C₁₋₅alkyl such as methyl. In another embodiment,d and e are 1, and f is 0, i.e., R⁶ and R⁷ are taken together to form a2,5-diaza-bicyclo[2.2.1]heptane ring. Particular embodiments of the2,5-diaza-bicyclo[2.2.1]heptane ring include those where R⁹ is: —H; or—X⁹R^(9a), where X⁹ is —C₁₋₅alkylene such as —CH₂—, and R^(9a) is arylsuch as phenyl.

A particular group of compounds of interest are compounds of formula Iwherein a, b, and c are 0. Another group of compounds of interest arecompounds of formula I wherein W is —O—. A particular group of compoundsof interest are compounds of formula I where m is 0 and t is 1. Aparticular group of compounds of interest are compounds of formula Iwhere Z is —NHC(O)—, —N(CH₃)C(O)—, or —C(O)NH—. Other compounds ofinterest include those where Ar is phenylene, phenylene substituted withmethoxy, pyridylene, thienylene, pyrrolylene, or furylene, and inparticular where Ar is phen-1,3-ylene, phen-1,4-ylene,2-methoxyphen-1,4-ylene, 2,5-pyridylene, 2,5-thienylene,2,4-pyrrolylene, 2,5-pyrrolylene, or 2,5-furylene.

Combinations of the foregoing are also of interest. For example, onegroup of compounds of interest are compounds of formula I wherein m is0, t is 1, and W is —O—. These compounds can also be depicted by formulaIa:

where a, b, c, s, R¹⁻³, R⁶⁻⁷, Z, and Ar, are as defined for formula I.Another example of a group of compounds of interest are compounds offormula Ia wherein a, b, and c are 0; Z is selected from —NHC(O)—,—N(CH₃)C(O)—, and —C(O)NH—; and Ar is selected from phenylene, phenylenesubstituted with methoxy, pyridylene, thienylene, pyrrolylene, andfurylene.

In addition, particular compounds of formula I that are of interestinclude:

-   biphenyl-2-yl-carbamic acid    1-(2-{[4-(4-acetylpiperazin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(4-aminomethylbenzoyl)methylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(4-{[(furan-2-carbonyl)amino]methyl}benzoyl)    methylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(acetylaminomethyl)benzoyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl-(4-{[(pyridine-4-carbonyl)amino]methyl}benzoyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[(cyclopropanecarbonylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl-(4-{[(thiophene-2-carbonyl)amino]methyl}benzoyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[(cyclobutanecarbonylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(isopropylaminomethyl)benzoyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[(cyclopropylmethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl-(4-morpholin-4-ylmethylbenzoyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(4-{[(2-methanesulfonylethyl)methylamino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(4-ethylpiperazin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(4-isopropylpiperazin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[(ethylisopropylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(2,6-dimethylmorpholin-4-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(4-{[bis-(2-hydroxyethyl)amino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(tert-butylaminomethyl)benzoyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[(ethylmethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(4-{[bis-(2-ethoxyethyl)amino]methyl}benzoyl)    methylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-(methyl-{4-[(methylpyridin-3-ylmethylamino)    methyl]benzoyl}amino)ethyl]piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(4-{[bis(2-methoxyethyl)amino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(4-{[(2-hydroxyethyl)methylamino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(methyl-{4-[(methyl-pyridin-4-ylmethylamino)    methyl]benzoyl}amino)ethyl]piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[4-(2-methoxyethyl)piperazin-1-ylmethyl]benzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(4-ethanesulfonylpiperazin-1-ylmethyl)    benzoyl]methylamino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)    benzoyl]methylamino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[(2-hydroxyethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{methyl-[4-(4-pyridin-4-ylpiperazin-1-ylmethyl)    benzoyl]amino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(4-dimethylcarbamoylmethylpiperazin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{methyl-[4-(4-pyridin-4-ylmethylpiperazin-1-ylmethyl)benzoyl]amino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(methyl-{4-[4-(2-oxo-2-pyrrolidin-1-ylethyl)    piperazin-1-ylmethyl]benzoyl}amino)ethyl]piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[(2-hydroxyethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(4-ethylaminomethylbenzoyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid 1-{2-[(4-cyclopropylaminomethylbenzoyl)    methylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[(2-methoxyethylamino)methyl]beenzoyl}methyl    amino)ethyl]piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{methyl-[4-(3-oxopiperazin-1-ylmethyl)benzoyl]amino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(4-acetyl-[1,4]diazepan-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[4-(4-hydroxyphenyl)piperazin-1-ylmethyl]benzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[(carbamoylmethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[4-(4-dimethylcarbamoylpiperazin-1-ylmethyl)    benzoyl]methylamino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-(methyl-{4-[4-(pyrrolidine-1-carbonyl)piperazin-1-ylmethyl]benzoyl}amino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(methyl-{4-[4-(piperidine-1-carbonyl)piperazin-1-ylmethyl]benzoyl}amino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(methyl-{4-[4-(morpholine-4-carbonyl)piperazin-1-ylmethyl]benzoyl}amino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(4-aminomethylbenzoylamino)ethyl]piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-{2-[3-((1R,4R)-5-benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)benzylcarbamoyl]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-aminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-{[(pyridin-4-ylmethyl)amino]methyl}benzylcarbamoyl)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{3-[(furan-2-ylmethylmethylamino)methyl]benzylcarbamoyl}ethyl)piperidin-4-yl    ester;-   {[3-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionylamino}methyl)    benzyl]methylamino}acetic acid;-   biphenyl-2-ylcarbamic acid    1-[2-(3-cyclobutylaminomethylbenzylcarbamoyl) ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-cyclopropylaminomethylbenzylcarbamoyl) ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-morpholin-4-ylmethylbenzylcarbamoyl)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-methylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-dimethylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{methyl-[3-(4-methylaminomethylphenyl)    propionyl]amino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[3-(4-ethylaminomethylphenyl)propionyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(4-aminomethylphenylcarbamoyl)ethyl]piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(4-trifluoromethylbenzenesulfonylamino)    methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(butane-1-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(2-fluorobenzenesulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(quinoline-8-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid 1-{2-[4-(ethanesulfonylaminomethyl)    phenylcarbamoyl]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(2,6-dichlorobenzenesulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(toluene-4-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(thiophene-2-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid 1-{2-[4-(benzenesulfonylaminomethyl)    phenylcarbamoyl]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid 1-{2-[4-(methanesulfonylaminomethyl)    phenylcarbamoyl]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-{2-[4-(trifluoromethanesulfonylaminomethyl)    phenylcarbamoyl]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(propane-1-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(propane-2-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(4-{[(pyridin-2-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(4-{[(pyridin-3-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(4-{[(pyridin-4-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(4-{[(benzo[1,3]dioxol-5-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(4-{[(1H-indol-7-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[4-(isobutylaminomethyl)phenylcarbamoyl]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(4-{[(thiophen-2-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(3,3,3-trifluoropropylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(2-methylaminoethanesulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[3-(4-methylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[3-(4-ethylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{3-[4-(isopropylaminomethyl)phenyl]propionylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid 1-{2-[3-(4-cyclopropylaminomethylphenyl)    propionylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-{4-[(cyclopropylmethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid 1-{2-[3-(4-cyclopentylaminomethylphenyl)    propionylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-{4-[(2-hydroxyethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-{4-[(2-methoxyethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{3-[4-(4-acetyl-[1,4]diazepan-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{3-[4-(4-acetylpiperazin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-{4-[(carbamoylmethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{3-[4-(4-dimethylcarbamoylmethylpiperazin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl    ester;-   4-[4-(2-{2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethylcarbamoyl}ethyl)    benzyl]piperazine-1-carboxylic acid methyl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{3-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)    phenyl]propionylamino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-{2-[3-(4-{[bis-(2-hydroxyethyl)amino]methyl}phenyl)propionylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{3-[4-(4-dimethylcarbamoylpiperazin-1-ylmethyl)    phenyl]propionylamino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-{4-[4-(pyrrolidine-1-carbonyl)piperazin-1-ylmethyl]phenyl}propionylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-{4-[4-(piperidine-1-carbonyl)piperazin-1-ylmethyl]phenyl}propionylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(3-{4-[4-(morpholine-4-carbonyl)piperazin-1-ylmethyl]phenyl}propionylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[2-(4-methylaminomethylphenyl)acetylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[2-(4-ethylaminomethylphenyl)acetylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(2-{4-[(2-hydroxyethylamino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(2-{4-[(2-methoxyethylamino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(2-{4-[(carbamoylmethylamino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{2-[4-(4-dimethylcarbamoylpiperazin-1-ylmethyl)phenyl]acetylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(2-methoxy-4-methylaminomethylbenzoyl)    methylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[2-methoxy-4-(3-oxopiperazin-1-ylmethyl)    benzoyl]methylamino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-({4-[(2-hydroxyethylamino)methyl]-2-methoxybenzoyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-(2-methoxy-4-methylaminomethylbenzoylamino)    ethyl]piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-{2-[2-methoxy-4-(3-oxopiperazin-1-ylmethyl)    benzoylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{4-[(2-hydroxyethylamino)methyl]-2-methoxybenzoylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl(5-methylaminomethylpyridine-2-carbonyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(5-diethylaminomethylpyridine-2-carbonyl)    methylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-({5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl(5-morpholin-4-ylmethylpyridine-2-carbonyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(5-{[(furan-2-ylmethyl)amino]methyl}pyridine-2-carbonyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-formylpiperazin-1-ylmethyl)pyridine-2-carbonyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(5-{[bis-(2-hydroxyethyl)amino]methyl}pyridine-2-carbonyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{methyl-[5-(3-oxo-piperazin-1-ylmethyl)pyridine-2-carbonyl]amino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-acetyl-[1,4]diazepan-1-ylmethyl)pyridine-2-carbonyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-acetylpiperazin-1-ylmethyl)pyridine-2-carbonyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-methanesulfonylpiperazin-1-ylmethyl)    pyridine-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;-   4-[6-({2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}methylcarbamoyl)    pyridin-3-ylmethyl]piperazine-1-carboxylic acid methyl ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl-(5-methylaminomethylthiophene-2-carbonyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(5-diethylaminomethylthiophene-2-carbonyl)    methylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-({5-[(2-hydroxyethylamino)methyl]thiophene-2-carbonyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl-(5-morpholin-4-ylmethylthiophene-2-carbonyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(5-{[(furan-2-ylmethyl)amino]methyl}thiophene-2-carbonyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-formylpiperazin-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(5-{[bis-(2-hydroxy-ethyl)amino]methyl}thiophene-2-carbonyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-yl-carbamic acid    1-(2-{methyl-[5-(3-oxopiperazin-1-ylmethyl)    thiophene-2-carbonyl]amino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-acetyl-[1,4]diazepan-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl    ester;-   4-[5-({2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}methylcarbamoyl)    thiophen-2-ylmethyl]piperazine-1-carboxylic acid methyl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)    thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-acetylpiperazin-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-methanesulfonylpiperazin-1-ylmethyl)    thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(5-methylaminomethylthiophene-2-carbonyl)    amino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-({5-[(2-hydroxyethylamino)methyl]thiophene-2-carbonyl}amino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl(4-methylaminomethyl-1H-pyrrole-2-carbonyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl-(5-methylaminomethyl-1H-pyrrole-2-carbonyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-acetylpiperazin-1-ylmethyl)-1H-pyrrole-2-carbonyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-[2-({5-[(2-hydroxyethylamino)methyl]-1H-pyrrole-2-carbonyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl(5-methylaminomethylfuran-2-carbonyl)    amino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(5-diethylaminomethylfuran-2-carbonyl)    methylamino]ethyl}piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-[2-({5-[(2-hydroxyethylamino)methyl]furan-2-carbonyl}methylamino)ethyl]piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[methyl(5-morpholin-4-ylmethylfuran-2-carbonyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(5-{[(furan-2-ylmethyl)amino]methyl}furan-2-carbonyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-formylpiperazin-1-ylmethyl)furan-2-carbonyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-{2-[(5-{[bis-(2-hydroxyethyl)amino]methyl}furan-2-carbonyl)methylamino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-yl-carbamic acid    1-(2-{methyl-[5-(3-oxopiperazin-1-ylmethyl)furan-2-carbonyl]amino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-acetyl[1,4]diazepan-1-ylmethyl)furan-2-carbonyl]ethylamino}ethyl)piperidin-4-yl    ester;-   4-[5-({2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}methylcarbamoyl)    furan-2-ylmethyl]piperazine-1-carboxylic acid methyl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)    furan-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-acetylpiperazin-1-ylmethyl)furan-2-carbonyl]methylamino}ethyl)piperidin-4-yl    ester;-   biphenyl-2-ylcarbamic acid    1-(2-{[5-(4-methanesulfonylpiperazin-1-ylmethyl)    furan-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;-   biphenyl-2-yl-carbamic acid    1-{2-[(5-aminomethylfuran-2-carbonyl)amino]ethyl}piperidin-4-yl    ester;-   biphenyl-2-yl-carbamic acid    1-{2-[(5-methylaminomethylfuran-2-carbonyl)amino]ethyl}piperidin-4-yl    ester; and-   biphenyl-2-ylcarbamic acid    1-[2-({5-[(2-hydroxyethylamino)methyl]furan-2-carbonyl}amino)ethyl]piperidin-4-yl    ester;

or a pharmaceutically acceptable salt or solvate thereof.

DEFINITIONS

When describing the compounds, compositions, methods and processes ofthe invention, the following terms have the following meanings unlessotherwise indicated.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched. Unless otherwise defined, such alkyl groupstypically contain from 1 to 10 carbon atoms. Representative alkyl groupsinclude, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl and the like.

The term “alkylene” means a divalent saturated hydrocarbon group whichmay be linear or branched. Unless otherwise defined, such alkylenegroups typically contain from 1 to 10 carbon atoms. Representativealkylene groups include, by way of example, methylene, ethane-1,2-diyl(“ethylene”), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl and the like.

The term “alkoxy” means a monovalent group of the formula (alkyl)-O—,where alkyl is as defined herein. Representative alkoxy groups include,by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,sec-butoxy, isobutoxy, tert-butoxy and the like.

The term “alkenyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon double bonds. Unless otherwisedefined, such alkenyl groups typically contain from 2 to 10 carbonatoms. Representative alkenyl groups include, by way of example,ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl and thelike. The term “alkenylene” means a divalent alkenyl group.

The term “alkynyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon triple bonds. Unless otherwisedefined, such alkynyl groups typically contain from 2 to 10 carbonatoms. Representative alkynyl groups include, by way of example,ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like. The term“alkynylene” means a divalent alkynyl group.

The term “aryl” means a monovalent aromatic hydrocarbon having a singlering (i.e., phenyl) or fused rings (i.e., naphthalene). Unless otherwisedefined, such aryl groups typically contain from 6 to 10 carbon ringatoms. Representative aryl groups include, by way of example, phenyl andnaphthalene-1-yl, naphthalene-2-yl, and the like. The term “arylene”means a divalent aryl group.

The term “cycloalkyl” means a monovalent saturated carbocyclichydrocarbon group. Unless otherwise defined, such cycloalkyl groupstypically contain from 3 to 10 carbon atoms. Representative cycloalkylgroups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl and the like. The term “cycloalkylene” means a divalentcycloalkyl group.

The term “halo” means fluoro, chloro, bromo and iodo.

The term “heteroaryl” means a monovalent aromatic group having a singlering or two fused rings and containing in the ring at least oneheteroatom (typically 1 to 3 heteroatoms) selected from nitrogen, oxygenor sulfur. Unless otherwise defined, such heteroaryl groups typicallycontain from 5 to 10 total ring atoms. Representative heteroaryl groupsinclude, by way of example, monovalent species of pyrrole, imidazole,thiazole, oxazole, furan, thiophene, triazole, pyrazole, isoxazole,isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine,indole, benzofuran, benzothiophene, benzimidazole, benzthiazole,quinoline, isoquinoline, quinazoline, quinoxaline and the like, wherethe point of attachment is at any available carbon or nitrogen ringatom. The term “heteroarylene” means a divalent heteroaryl group.

The term “heterocyclyl” or “heterocyclic” means a monovalent saturatedor unsaturated (non-aromatic) group having a single ring or multiplecondensed rings and containing in the ring at least one heteroatom(typically 1 to 3 heteroatoms) selected from nitrogen, oxygen or sulfur.Unless otherwise defined, such heterocyclic groups typically containfrom 2 to 9 total ring carbon atoms. Representative heterocyclic groupsinclude, by way of example, monovalent species of pyrrolidine,imidazolidine, pyrazolidine, piperidine, 1,4-dioxane, morpholine,thiomorpholine, piperazine, 3-pyrroline and the like, where the point ofattachment is at any available carbon or nitrogen ring atom. The term“heterocyclene” means a divalent heterocyclyl or heterocyclic group.

When a specific number of carbon atoms is intended for a particular termused herein, the number of carbon atoms is shown preceding the term. Forexample, the term “(1-5C)alkyl” or “C₁₋₅alkyl” means an alkyl grouphaving from 1 to 5 carbon atoms.

The term “pharmaceutically acceptable salt” means a salt which isacceptable for administration to a patient, such as a mammal (e.g.,salts having acceptable mammalian safety for a given dosage regime).Such salts can be derived from pharmaceutically acceptable inorganic ororganic bases and from pharmaceutically acceptable inorganic or organicacids. Salts derived from pharmaceutically acceptable inorganic basesinclude ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,manganic, manganous, potassium, sodium, zinc and the like. Particularlypreferred are ammonium, calcium, magnesium, potassium and sodium salts.Salts derived from pharmaceutically acceptable organic bases includesalts of primary, secondary and tertiary amines, including substitutedamines, cyclic amines, naturally-occurring amines and the like, such asarginine, betaine, caffeine, choline, N,N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperadine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. Salts derived frompharmaceutically acceptable acids include acetic, ascorbic,benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic,edisylic, fumaric, gentisic, gluconic, glucoronic, glutamic, hippuric,hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic,malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic,naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic, nicotinic,nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulfuric,tartaric, p-toluenesulfonic, xinafoic and the like. Particularlypreferred are citric, hydrobromic, hydrochloric, isethionic, maleic,naphthalene-1,5-disulfonic, phosphoric, sulfuric and tartaric acids.

The term “salt thereof” means a compound formed when the hydrogen of anacid is replaced by a cation, such as a metal cation or an organiccation and the like. Preferably, the salt is a pharmaceuticallyacceptable salt, although this is not required for salts of intermediatecompounds that are not intended for administration to a patient.

The term “solvate” means a complex or aggregate formed by one or moremolecules of a solute, i.e. a compound of formula I or apharmaceutically acceptable salt thereof, and one or more molecules of asolvent. Such solvates are typically crystalline solids having asubstantially fixed molar ratio of solute and solvent. Representativesolvents include, by way of example, water, methanol, ethanol,isopropanol, acetic acid and the like. When the solvent is water, thesolvate formed is a hydrate.

It will be appreciated that the term “or a pharmaceutically acceptablesalt or solvate or stereoisomer thereof” is intended to include allpermutations of salts, solvates and stereoisomers, such as a solvate ofa pharmaceutically acceptable salt of a stereoisomer of a compound offormula I.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need of treatment.For example, a therapeutically effective amount for antagonizing amuscarinic receptor is that amount which will achieve the desiredantagonizing effect. Similarly, a therapeutically effective amount fortreating a pulmonary disorder is the amount that will achieve thedesired therapeutic result, which may be disease prevention,amelioration, suppression or alleviation, as described below.

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition (such as COPD) in a patient,such as a mammal (particularly a human) that includes: (a) preventingthe disease or medical condition from occurring, i.e., prophylactictreatment of a patient; (b) ameliorating the disease or medicalcondition, i.e., eliminating or causing regression of the disease ormedical condition in a patient; (c) suppressing the disease or medicalcondition, i.e., slowing or arresting the development of the disease ormedical condition in a patient; or (d) alleviating the symptoms of thedisease or medical condition in a patient.

The term “leaving group” means a functional group or atom which can bedisplaced by another functional group or atom in a substitutionreaction, such as a nucleophilic substitution reaction. By way ofexample, representative leaving groups include chloro, bromo and iodogroups; sulfonic ester groups, such as mesylate, tosylate, brosylate,nosylate and the like; and acyloxy groups, such as acetoxy,trifluoroacetoxy and the like.

General Synthetic Procedures

The biphenyl compounds of the invention can be prepared from readilyavailable starting materials using the following general methods, theprocedures set forth in the Examples, or by using other methods,reagents, and starting materials that are readily available to those ofordinary skill in the art. Although a particular embodiment of thepresent invention may be shown or described herein, those skilled in theart will recognize that all embodiments or aspects of the presentinvention can be prepared using the methods described herein or by usingother methods, reagents and starting materials known to those skilled inthe art. It will also be appreciated that where typical or preferredprocess conditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. While the optimumreaction conditions may vary depending on the particular reactants orsolvent used, such conditions can be readily determined by one skilledin the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary or desired to preventcertain functional groups from undergoing undesired reactions. Thechoice of a suitable protecting group for a particular functional groupas well as suitable conditions for protection and deprotection of suchfunctional groups are well-known in the art. Functional groups which maybe protected include, by way of example, carboxylic acid groups, aminogroups, hydroxyl groups, thiol groups, carbonyl groups and the like.Protecting groups other than those illustrated in the proceduresdescribed herein may be used, if desired. Representative protectinggroups for carboxylic acids include esters, amides and hydrazides; foramino groups, carbamates and amides; for hydroxyl groups, ethers andesters; for thiol groups, thioethers and thioesters; for carbonylgroups, acetals and ketals; and the like. Exemplary protecting groupsare listed below, and other groups as well as details of theirintroduction and removal, are described in T. W. Greene and G. M. Wuts,Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York,1999, and references cited therein.

Amino-protecting groups are suitable for preventing undesired reactionsat an amino group, and include, but are not limited to,tert-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl (Cbz),9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS),tert-butyldimethylsilyl (TBS), and the like. Carboxy-protecting groupsare suitable for preventing undesired reactions at a carboxy group, andinclude, but are not limited to, esters, such as methyl, ethyl,tert-butyl, benzyl (Bn), p-methoxybenzyl (PMB), 9-fluroenylmethyl (Fm),trimethylsilyl (TMS), tert-butyldimethylsilyl (TBS), diphenylmethyl(benzhydryl, DPM) and the like. Hydroxyl-protecting groups are suitablefor preventing undesirable reactions at a hydroxyl group, and include,but are not limited to, silyl groups including tri(1-6C)alkylsilylgroups, such as trimethylsilyl (TMS), triethylsilyl (TES),tert-butyldimethylsilyl (TBS) and the like; esters (acyl groups)including (1-6C)alkanoyl groups, such as formyl, acetyl and the like;arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB),9-fluorenylmethyl (Fm), diphenylmethyl (benzhydryl, DPM) and the like.Additionally, two hydroxyl groups can also be protected as an alkylidenegroup, such as prop-2-ylidine, formed, for example, by reaction with aketone, such as acetone.

By way of illustration, the compounds of formula I can be prepared by aprocess comprising:

(a) reacting a compound of formula II:

or a salt thereof, with a compound of formula III:

wherein L¹ represents a leaving group; or

(b) coupling a compound of formula IVa:

or a reactive derivative thereof, with a compound of formula Va:

or coupling a compound of formula IVb:

with a compound of formula Vb:

or a reactive derivative thereof; or

(c) reacting a compound of formula VI:

wherein L² represents a leaving group, with a compound of formula VII:

or

(d) reacting a compound of formula II with a compound of formula VIII:

in the presence of a reducing agent; or

(e) reacting a compound of formula IX:

with a compound of formula VII in the presence of a reducing agent; andthen

(f) removing any protecting groups that may be present to provide acompound of formula I; and optionally, forming a pharmaceuticallyacceptable salt thereof.

Generally, if a salt of one of the starting materials is used in theprocesses described above, such as an acid addition salt, the salt istypically neutralized before or during the reaction process. Thisneutralization reaction is typically accomplished by contacting the saltwith one molar equivalent of a base for each molar equivalent of acidaddition salt.

In process (a), the reaction between the compounds of formula II andIII, the leaving represented by L¹ can be, for example, halo, such aschloro, bromo or iodo, or a sulfonic ester group, such as mesylate ortosylate. The reaction is conveniently performed in the presence of abase, for example, a tertiary amine such as diisopropylethylamine.Convenient solvents include nitriles, such as acetonitrile. The reactionis conveniently conducted at a temperature in the range of from 0° C. to100° C.

Compounds of formula II are generally known in the art, or can beprepared by deprotecting a compound of formula X:

wherein P¹ represents an amino-protecting group, such as a benzyl group.Benzyl groups are conveniently removed by reduction, using a hydrogen orammonium formate and a Group VIII metal catalyst, such as palladium.When W represents NW^(a), the hydrogenation is conveniently performedusing Pearlman's catalyst (Pd(OH)₂).

Compounds of formula X can be prepared by reacting an isocyanatecompound of formula XI with a compound of formula XII:

Compounds of formula III can be prepared starting from a correspondingcompound in which L¹ represents a hydroxyl group, for example, byreaction of a halogenating agent, such as thionyl chloride, to afford acompound of formula III in which L¹ represents halo, such as chloro.Compounds in which L¹ represents a hydroxyl group may be prepared, forexample, by reacting a compound of formula Vb with an appropriateamino-substituted alcohol, such as 2-aminoethanol or 3-aminopropan-1-ol.

In process (b), the term “reactive derivative” of compound IVa or Vb isintended to mean that the carboxylic acid is activated, for example, byforming an anhydride or carboxylic acid halide, such as a carboxylicacid chloride. Alternatively, the carboxylic acid can be activated usingconventional carboxylic acid/amine coupling reagents, suchcarbodiimides, O-(7-azabenzotriazol-1-yl-N,N,N′,N′ tetramethyluroniumhexafluorophosphate (HATU) and the like. This reaction is convenientlyperformed under conventional amide bond-forming conditions. The processis conveniently conducted at a temperature in the range of from −10° C.to 100° C.

Compounds of formula IVa can be prepared by reacting a compound offormula II with a compound of formula XIII:L³-CH₂(CH₂)_(m)CH₂COOP²  XIIIwherein L³ represents a leaving group including, for example, halo, suchas chloro, bromo or iodo, or a sulfonic ester group, such as mesylate ortosylate; and P² represents a hydrogen atom or a carboxyl-protectinggroup, such as a (1-4C)alkyl group. If necessary, thecarboxyl-protecting group P², is then removed, for example, byhydrolysis under conventional conditions, such as by using lithiumhydroxide.

Compounds of formula Va can be prepared by reacting a compound offormula VII with a compound of formula XIV:

wherein P³ represents hydrogen or an amino-protecting group, such astert-butoxycarbonyl, and L⁴ represents a leaving group including, forexample, halo, such as chloro, bromo or iodo, or a sulfonic ester group,such as mesylate or tosylate; followed if necessary, by removing anamino-protecting group P³. Alternatively, such compounds can be preparedby reductive amination of a compound of formula XV:

using a compound of formula VII. The reducing agent may be, for example,hydrogen in the presence of a Group VIII metal catalyst, such aspalladium, or a metal hydride reducing agent, such as a borohydride,including sodium triacetoxyborohydride. Convenient solvents includealcohols, such as methanol. The reaction is conveniently performed at atemperature in the range of from 0° C. to 100° C.

Compounds of formula IVb can be prepared by reacting a compound offormula II with a compound of formula XVI:C(O)H(CH₂)_(m)CH₂NR⁴P⁴  XVIwherein P⁴ represents hydrogen or an amino-protecting group, such asbenzyl, in the presence of a reducing agent, such as sodiumtriacetoxyborohydride, followed if necessary by removing theamino-protecting group P⁴ by, for example, hydrogenation in the presenceof palladium.

Compounds of formula Vb can be prepared by reacting a compound offormula VII with a compound of formula XVII:

wherein P⁵ represents hydrogen or a carboxyl-protecting group, such asmethyl or ethyl, and L⁵ represents a leaving group, followed ifnecessary by removing the carboxyl protecting group P⁵. Alternatively,such compounds can be prepared by reductive amination of a compound offormula XVIII with a compound of formula VII:

The reducing agent may be, for example, hydrogen in the presence of aGroup VIII metal catalyst, such as palladium, or a metal hydridereducing agent, such as a borohydride, including sodiumtriacetoxyborohydride. Convenient solvents include alcohols, such asmethanol. The reaction is conveniently performed at a temperature in therange of from 0° C. to 100° C.

Referring to process (c), the leaving group represented by L² can be,for example, halo, such as chloro, bromo or iodo, or a sulfonic estergroup, such as mesylate or tosylate. This reaction is convenientlyperformed in the presence of a base, for example, a tertiary amine suchas diisopropylethylamine. Convenient solvents include nitriles, such asacetonitrile. The reaction is conveniently conducted at a temperature inthe range of from 0° C. to 100° C. The compounds of formula VI can beprepared by reacting a compound of formula IVa with a compound offormula XIX:

or by reacting a compound of formula IVb with a compound of formula XX:

The reaction is conveniently performed following, for example, themethod of process (b) described herein. Compounds of formula VII aregenerally known or can be prepared from readily available startingmaterials using well-known synthetic methods.

In process (d), the reducing agent may be, for example, hydrogen in thepresence of a Group VIII metal catalyst, such as palladium, or a metalhydride reducing agent, such as a borohydride, including sodiumtriacetoxyborohydride, optionally used in combination with a titaniumtetraalkoxide, such as titanium tetraisopropoxide. Convenient solventsinclude alcohols, such as methanol and halogenated hydrocarbons, such asdichloromethane. The reaction is conveniently performed at a temperaturein the range of from 0° C. to 100° C.

The compound of formula VIII may be prepared by oxidizing a compoundcorresponding to formula III in which L¹ represents a hydroxyl group.Such oxidation reactions can be conducted, for example, using sulfurdioxide pyridine complex in dimethylsulfoxide in the presence of atertiary amine, such as diisopropylethylamine.

In process (e), the reduction is preformed as described for process (d).

Compounds of formula IX may be prepared by reacting a compound offormula IVb with a compound of formula XXI:

in the presence of a carboxylic acid/amine coupling agent, such as1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and1-hydroxybenzotriazole hydrate (HOBT) and the like.

As will be apparent to those skilled in the art, compounds of formula Iprepared by any of steps (a) to (f) herein may be further derivatized toform other compounds of formula I using methods and reagents well-knownin the art. By way of illustration, a compound of formula I may bereacted with bromine to afford a corresponding compound of formula I inwhich R², for example, represents a bromo group. Additionally, acompound of formula I in which R⁴ represents a hydrogen atom may bealkylated to afford a corresponding compound of formula I in which R⁴represents a (1-4C) alkyl group.

Further details regarding specific reaction conditions and otherprocedures for preparing representative compounds of the invention orintermediates thereof are described in the Examples set forth below.

Pharmaceutical Compositions and Formulations

The compounds of the invention are typically administered to a patientin the form of a pharmaceutical composition or formulation. Suchcompositions may be administered by any acceptable route ofadministration including, but not limited to, inhaled, oral, nasal,topical (including transdermal) and parenteral modes of administration.It will be understood that any form of the compound, i.e., free base,pharmaceutically acceptable salt, solvate, etc., that is suitable forthe particular mode of administration can be used in the compositionsdescribed herein.

Accordingly, in one embodiment, the invention is directed to apharmaceutical composition comprising a pharmaceutically acceptablecarrier or excipient and a therapeutically effective amount of acompound of formula I, or a pharmaceutically acceptable salt or solvateor stereoisomer thereof. The pharmaceutical composition may containother therapeutic and/or formulating agents if desired.

The compositions of the invention typically contain a therapeuticallyeffective amount of a compound of formula I or a pharmaceuticallyacceptable salt or solvate or stereoisomer thereof, as the active agent.Typically, the composition will contain from about 0.01-95% by weight ofthe active agent; including, from about 0.01-30% by weight; such as fromabout 0.01-10% by weight of the active agent.

Any conventional carrier or excipient may be used in the compositions ofthe invention. The choice of a particular carrier or excipient, orcombination of carriers or excipients, will depend on the mode ofadministration being used to treat a particular patient or type ofmedical condition or disease state. In this regard, the preparation of asuitable composition for a particular mode of administration is wellwithin the scope of those skilled in the pharmaceutical arts.Additionally, the ingredients for such compositions are commerciallyavailable from, for example, Sigma, P.O. Box 14508, St. Louis, Mo.63178. By way of further illustration, conventional formulationtechniques are described in Remington: The Science and Practice ofPharmacy, 20^(th) Edition, Lippincott Williams & White, Baltimore, Md.(2000); and H. C. Ansel et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, 7^(th) Edition, Lippincott Williams & White,Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients, such as cocoa butter andsuppository waxes; oils, such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil; glycols, such aspropylene glycol; polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar;) buffering agents, such as magnesium hydroxide and aluminumhydroxide; (alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; compressedpropellant gases, such as chlorofluorocarbons and hydrofluorocarbons;and other non-toxic compatible substances employed in pharmaceuticalcompositions.

The compositions of the invention are typically prepared by thoroughlyand intimately mixing or blending a compound of formula I with apharmaceutically acceptable carrier and one or more optionalingredients. If necessary or desired, the resulting uniformly blendedmixture can then be shaped or loaded into tablets, capsules, pills,canisters, cartridges, dispensers and the like using conventionalprocedures and equipment.

In one embodiment, the pharmaceutical compositions of the invention aresuitable for inhaled administration. Suitable compositions for inhaledadministration will typically be in the form of an aerosol or a powder,and are generally administered using well-known delivery devices, suchas a nebulizer inhaler, a dry powder inhaler (DPI), a metered-doseinhaler (MDI) or similar delivery device.

In a specific embodiment of the invention, a pharmaceutical compositioncomprising the active agent is administered by inhalation using anebulizer inhaler. Such nebulizer devices typically produce a stream ofhigh velocity air that causes the composition comprising the activeagent to spray as a mist that is carried into the patient's respiratorytract. Accordingly, when formulated for use in a nebulizer inhaler, theactive agent is typically dissolved in a suitable carrier to form asolution. Alternatively, the active agent can be micronized and combinedwith a suitable carrier to form a suspension of micronized particles ofrespirable size, where micronized is typically defined as having about90% or more of the particles with a diameter of less than about 10 μm.Suitable nebulizer devices are commercially available, for example, byPARI GmbH (Starnberg, German). Other nebulizer devices include Respimat(Boehringer Ingelheim) and those described, for example, in U.S. Pat.No. 6,123,068 to Lloyd et al. and WO 97/12687 (Eicher et al.), thedisclosures of which are incorporated herein by reference in theirentirety. A representative pharmaceutical composition for use in anebulizer inhaler comprises an isotonic aqueous solution comprising fromabout 0.05 μg/mL to about 10 mg/mL of a compound of formula I or apharmaceutically acceptable salt or solvate or stereoisomer thereof.

In another specific embodiment of the invention, a pharmaceuticalcomposition comprising the active agent is administered by inhalationusing a DPI. Such DPIs typically administer the active agent as afree-flowing powder that is dispersed in a patient's air-stream duringinspiration. In order to achieve a free flowing powder, the active agentis typically formulated with a suitable excipient such as lactose orstarch. Micronization is a common method of reducing crystal size tothat suitable for pulmonary delivery. Typically, the active agent ismicronized and combined with a suitable carrier to form a suspension ofmicronized particles of respirable size, where “micronized particles” or“micronized form” means at least about 90% of the particles have adiameter of less than about 10 μm. Other methods of reducing particlesize may also be used such as fine milling, chopping, crushing,grinding, milling, screening, trituration, pulverization, and so forth,as long as the desired particle size can be obtained. A representativepharmaceutical composition for use in a DPI comprises dry lactose havinga particle size between about 1 μm and about 100 μm and micronizedparticles of a compound of formula I, or a pharmaceutically acceptablesalt or solvate or stereoisomer thereof. Such a dry powder formulationcan be made, for example, by combining the lactose with the active agentand then dry blending the components. Alternatively, if desired, theactive agent can be formulated without an excipient. The pharmaceuticalcomposition is then typically loaded into a dry powder dispenser, orinto inhalation cartridges or capsules for use with a dry powderdelivery device. Examples of DPI delivery devices include Diskhaler(GlaxoSmithKline, Research Triangle Park, N.C.) (see, e.g., U.S. Pat.No. 5,035,237 to Newell et al.); Diskus (GlaxoSmithKline) (see, e.g.,U.S. Pat. No. 6,378,519 to Davies et al.); Turbuhaler (AstraZeneca,Wilmington, Del.) (see, e.g., U.S. Pat. No. 4,524,769 to Wetterlin);Rotahaler (GlaxoSmithKline) (see, e.g., U.S. Pat. No. 4,353,365 toHallworth et al.); Handihaler (Boehringer Ingelheim); and thosedescribed in U.S. Pat. No. 5,415,162 to Casper et al., U.S. Pat. No.5,239,993 to Evans, and U.S. Pat. No. 5,715,810 to Armstrong et al., andreferences cited therein; the disclosures of which are incorporatedherein by reference in their entirety.

In yet another specific embodiment of the invention, the pharmaceuticalcomposition comprising the active agent is administered by inhalationusing an MDI, which typically discharges a measured amount of the activeagent or a pharmaceutically acceptable salt or solvate or stereoisomerthereof using compressed propellant gas. Accordingly, pharmaceuticalcompositions administered using an MDI typically comprise a solution orsuspension of the active agent in a liquefied propellant. Any suitableliquefied propellant may be employed including chlorofluorocarbons, suchas CCl₃F, and hydrofluoroalkanes (HFAs), such as1,1,1,2-tetrafluoroethane (HFA 134a) and1,1,1,2,3,3,3-heptafluoro-n-propane, (HFA 227). Formulations containingHFAs are generally preferred due to concerns about chlorofluorocarbonsaffecting the ozone layer. Additional optional components of HFAformulations include co-solvents, such as ethanol or pentane, andsurfactants, such as sorbitan trioleate, oleic acid, lecithin, andglycerin. See, for example, U.S. Pat. No. 5,225,183 to Purewal et al.,EP 0717987 A2 (Minnesota Mining and Manufacturing Company), and WO92/22286 (Minnesota Mining and Manufacturing Company), the disclosuresof which are incorporated herein by reference in their entirety. Arepresentative pharmaceutical composition for use in an MDI comprisesfrom about 0.01-5% by weight of a compound of formula I, or apharmaceutically acceptable salt or solvate or stereoisomer thereof;from about 0-20% by weight ethanol; and from about 0-5% by weightsurfactant; with the remainder being an HFA propellant. Suchcompositions are typically prepared by adding chilled or pressurizedhydrofluoroalkane to a suitable container containing the active agent,ethanol (if present) and the surfactant (if present). To prepare asuspension, the active agent is micronized and then combined with thepropellant. The formulation is then loaded into an aerosol canister,which forms a portion of a metered-dose inhaler device. Examples of MDIdevices developed specifically for use with HFA propellants aredescribed in U.S. Pat. No. 6,006,745 to Marecki and U.S. Pat. No.6,143,277 to Ashurst et al. Alternatively, a suspension formulation canbe prepared by spray drying a coating of surfactant on micronizedparticles of the active agent. See, for example, WO 99/53901 (GlaxoGroup Ltd.) and WO 00/61108 (Glaxo Group Ltd.). The disclosures of theaforementioned patents and publications are incorporated herein byreference in their entirety.

For additional examples of processes of preparing respirable particles,and formulations and devices suitable for inhalation dosing see U.S.Pat. No. 6,268,533 to Gao et al., U.S. Pat. No. 5,983,956 to Trofast,U.S. Pat. No. 5,874,063 to Briggner et al., and U.S. Pat. No. 6,221,398to Jakupovic et al.; and WO 99/55319 (Glaxo Group Ltd.) and WO 00/30614(AstraZeneca AB); the disclosures of which are incorporated herein byreference in their entirety.

In another embodiment, the pharmaceutical compositions of the inventionare suitable for oral administration. Suitable compositions for oraladministration may be in the form of capsules, tablets, pills, lozenges,cachets, dragees, powders, granules; or as a solution or a suspension inan aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilliquid emulsion; or as an elixir or syrup; and the like; each containinga predetermined amount of a compound of the present invention as anactive ingredient.

When intended for oral administration in a solid dosage form, i.e., ascapsules, tablets, pills and the like, the composition will typicallycomprise a compound of the invention as the active ingredient and one ormore pharmaceutically acceptable carriers, such as sodium citrate ordicalcium phosphate. The solid dosage forms may also comprise one ormore of the following: fillers or extenders, such as starches, lactose,sucrose, glucose, mannitol, and/or silicic acid; binders, such ascarboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; humectants, such as glycerol; disintegratingagents, such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and/or sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as cetyl alcoholand/or glycerol monostearate; absorbents, such as kaolin and/orbentonite clay; lubricants, such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, and/ormixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants can also be presentin the compositions of the invention. Examples of pharmaceuticallyacceptable antioxidants include: water-soluble antioxidants, such asascorbic acid, cysteine hydrochloride, sodium bisulfate, sodiummetabisulfate sodium sulfite and the like; oil-soluble antioxidants,such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylatedhydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, andthe like; and metal-chelating agents, such as citric acid,ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid,phosphoric acid, and the like. Coating agents for tablets, capsules,pills and like, include those used for enteric coatings, such ascellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP),hydroxypropyl methylcellulose phthalate, methacrylic acid-methacrylicacid ester copolymers, cellulose acetate trimellitate (CAT),carboxymethyl ethyl cellulose (CMEC), hydroxypropyl methyl celluloseacetate succinate (HPMCAS), and the like.

If desired, the compositions of the invention may also be formulated toprovide slow or controlled release of the active ingredient using, byway of example, hydroxypropyl methyl cellulose in varying proportions;or other polymer matrices, liposomes and/or microspheres.

In addition, the compositions of the invention may optionally containopacifying agents and may be formulated so that they release the activeingredient only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Liquid dosage formstypically comprise the active ingredient and an inert diluent, such as,for example, water or other solvents, solubilizing agents andemulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate,ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol,1,3-butylene glycol, oils (e.g., cottonseed, groundnut, corn, germ,olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol,polyethylene glycols and fatty acid esters of sorbitan, and mixturesthereof. Suspensions, in addition to the active ingredient, may containsuspending agents such as, for example, ethoxylated isostearyl alcohols,polyoxyethylene sorbitol and sorbitan esters, microcrystallinecellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth,and mixtures thereof.

When intended for oral administration, the compositions of the inventionare preferably packaged in a unit dosage form. The term “unit dosageform” means a physically discrete unit suitable for dosing a patient,i.e., each unit containing a predetermined quantity of active agentcalculated to produce the desired therapeutic effect either alone or incombination with one or more additional units. For example, such unitdosage forms may be capsules, tablets, pills, and the like.

The compounds of the invention can also be administered transdermallyusing known transdermal delivery systems and excipients. For example, acompound of the invention can be admixed with permeation enhancers, suchas propylene glycol, polyethylene glycol monolaurate,azacycloalkan-2-ones and the like, and incorporated into a patch orsimilar delivery system. Additional excipients including gelling agents,emulsifiers and buffers, may be used in such transdermal compositions ifdesired.

The compounds of the invention can also be co-administered with othertherapeutic agents. This combination therapy involves using a compoundof the invention combined with one or more of these secondary agents,either formulated together (e.g., packaged together in a singleformulation) or formulated separately (e.g., packaged as separate unitdosage forms). Methods of formulating multiple agents together in thesame formulation or in separate unit dosage forms, are well known in theart. The secondary agents can be used in the form of pharmaceuticallyacceptable salts or solvates, and if appropriate, as optically purestereoisomers.

The secondary therapeutic agent(s) can be selected from otherbronchodilators (e.g., PDE₃ inhibitors, adenosine 2b modulators and β₂adrenergic receptor agonists); anti-inflammatory agents (e.g., steroidalanti-inflammatory agents, such as corticosteroids; non-steroidalanti-inflammatory agents (NSAIDs), and PDE₄ inhibitors); othermuscarinic receptor antagonists (i.e., antichlolinergic agents);antiinfective agents (e.g., Gram positive and Gram negative antibioticsor antivirals); antihistamines; protease inhibitors; and afferentblockers (e.g., D₂ agonists and neurokinin modulators). One particularembodiment of the invention is directed to a composition comprising (a)a pharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of formula I or a pharmaceutically acceptable saltor solvate or stereoisomer thereof; and (b) a pharmaceuticallyacceptable carrier and a therapeutically effective amount of an agentselected from a steroidal anti-inflammatory agent such as acorticosteroid; a β₂ adrenergic receptor agonist; a phosphodiesterase-4inhibitor; or a combination thereof; wherein the compound of formula Iand the agent are formulated together or separately. In anotherembodiment, (b) is a pharmaceutically acceptable carrier and atherapeutically effective amount of a β₂ adrenergic receptor agonist anda steroidal anti-inflammatory agent.

Representative β₂ adrenergic receptor agonists include, but are notlimited to, salmeterol, salbutamol, formoterol, salmefamol, fenoterol,terbutaline, albuterol, isoetharine, metaproterenol, bitolterol,pirbuterol, levalbuterol and the like, or pharmaceutically acceptablesalts thereof. Other β₂ adrenergic receptor agonists that can be used incombination with the compounds of the invention include, but are notlimited to,3-(4-{[6-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethyl}amino)-hexyl]oxy}butyl)benzenesulfonamideand3-(-3-{[7-({(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}-amino)heptyl]oxy}-propyl)benzenesulfonamideand related compounds disclosed in WO 02/066422 (Glaxo Group Ltd.);3-[3-(4-{[6-([(2R)-2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl}amino)hexyl]oxy}butyl)-phenyl]imidazolidine-2,4-dioneand related compounds disclosed in WO 02/070490 (Glaxo Group Ltd.);3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)-benzenesulfonamide,3-(4-{[6-({(2S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)-benzenesulfonamide,3-(4-{[6-({(2R/S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]oxy}butyl)-benzenesulfonamide,N-(tert-butyl)-3-(4-{[6-({(2R)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]-oxy}butyl)benzenesulfonamide,N-(tert-butyl)-3-(4-{[6-({(2S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)-hexyl]oxy}butyl)-benzenesulfonamide,N-(tert-butyl)-3-(4-{[6-({(2R/S)-2-[3-(formylamino)-4-hydroxyphenyl]-2-hydroxyethyl}amino)hexyl]-oxy}butyl)benzenesulfonamide and related compounds disclosed inWO 02/076933 (Glaxo Group Ltd.);4-{(1R)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenoland related compounds disclosed in WO 03/024439 (Glaxo Group Ltd.);N-{2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamineand related compounds disclosed in U.S. Pat. No. 6,576,793 to Moran etal.;N-{2-[4-(3-phenyl-4-methoxyphenyl)aminophenyl]ethyl}-(R)-2-hydroxy-2-(8-hydroxy-2(1H)-quinolinon-5-yl)ethylamineand related compounds disclosed in U.S. Pat. No. 6,653,323 to Moran etal.; and pharmaceutically acceptable salts thereof. In a particularembodiment, the β₂-adrenoreceptor agonist is a crystallinemonohydrochloride salt ofN-{2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamine. When employed, the β₂-adrenoreceptor agonist will be presentin the pharmaceutical composition in a therapeutically effective amount.Typically, the β₂-adrenoreceptor agonist will be present in an amountsufficient to provide from about 0.05-500 μg per dose. The disclosuresof the aforementioned patents and publications are incorporated hereinby reference in their entirety.

Representative steroidal anti-inflammatory agents include, but are notlimited to, methyl prednisolone, prednisolone, dexamethasone,fluticasone propionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydrofuran-3S-yl) ester, beclomethasone esters (e.g.,the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g., the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,ST-126 and the like, or pharmaceutically-acceptable salts thereof. Whenemployed, the steroidal anti-inflammatory agent will be present in thepharmaceutical composition in a therapeutically effective amount.Typically, the steroidal anti-inflammatory agent will be present in anamount sufficient to provide from about 0.05-500 μg per dose.

An exemplary combination is a compound of formula I, or pharmaceuticallyacceptable salt or solvate or stereoisomer thereof, co-administered withsalmeterol as the β₂ adrenergic receptor agonist, and fluticasonepropionate as the steroidal anti-inflammatory agent. Another exemplarycombination is a compound of formula I, or pharmaceutically acceptablesalt or solvate or stereoisomer thereof, co-administered with acrystalline monohydrochloride salt ofN-{2-[4-((R)-2-hydroxy-2-phenylethylamino)phenyl]ethyl}-(R)-2-hydroxy-2-(3-formamido-4-hydroxyphenyl)ethylamineas the β₂-adrenoreceptor agonist, and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxoandrosta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester as the steroidal anti-inflammatory agent.

Other suitable combinations include, for example, otheranti-inflammatory agents, e.g., NSAIDs (such as sodium cromoglycate;nedocromil sodium; phosphodiesterase (PDE) inhibitors (e.g.,theophylline, PDE4 inhibitors or mixed PDE3/PDE4 inhibitors);leukotriene antagonists (e.g., monteleukast); inhibitors of leukotrienesynthesis; iNOS inhibitors; protease inhibitors, such as tryptase andelastase inhibitors; beta-2 integrin antagonists and adenosine receptoragonists or antagonists (e.g., adenosine 2a agonists); cytokineantagonists (e.g., chemokine antagonists such as, an interleukinantibody (αIL antibody), specifically, an αIL-4 therapy, an αIL-13therapy, or a combination thereof); or inhibitors of cytokine synthesis.

Representative phosphodiesterase-4 (PDE4) inhibitors or mixed PDE3/PDE4inhibitors include, but are not limited to cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one;cis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid and the like, or pharmaceutically acceptable salts thereof. Otherrepresentative PDE4 or mixed PDE4/PDE3 inhibitors include AWD-12-281(elbion); NCS-613 (INSERM); D-4418 (Chiroscience and Schering-Plough);CI-1018 or PD-168787 (Pfizer); benzodioxole compounds disclosed inWO99/16766 (Kyowa Hakko); K-34 (Kyowa Hakko); V-11294A (Napp);roflumilast (Byk-Gulden); pthalazinone compounds disclosed in WO99/47505(Byk-Gulden); Pumafentrine (Byk-Gulden, now Altana); arofylline(Almirall-Prodesfarma); VM554/UM565 (Vemalis); T-440 (Tanabe Seiyaku);and T2585 (Tanabe Seiyaku).

Representative muscarinic antagonists (i.e., anticholinergic agents)that can be used in combination with, and in addition to, the compoundsof the invention include, but are not limited to, atropine, atropinesulfate, atropine oxide, methylatropine nitrate, homatropinehydrobromide, hyoscyamine (d, l) hydrobromide, scopolamine hydrobromide,ipratropium bromide, oxitropium bromide, tiotropium bromide,methantheline, propantheline bromide, anisotropine methyl bromide,clidinium bromide, copyrrolate (Robinul), isopropaminde iodide,mepenzolate bromide, tridihexethyl chloride (Pathilone), hexocycliummethylsulfate, cyclopentolate hydrochloride, tropicamide,trihexyphenidyl hydrochloride, pirenzepine, telenzepine, AF-DX 116 andmethoctramine and the like, or a pharmaceutically acceptable saltthereof; or, for those compounds listed as a salt, alternatepharmaceutically acceptable salt thereof.

Representative antihistamines (i.e., H₁-receptor antagonists) include,but are not limited to, ethanolamines, such as carbinoxamine maleate,clemastine fumarate, diphenylhydramine hydrochloride and dimenhydrinate;ethylenediamines, such as pyrilamine amleate, tripelennaminehydrochloride and tripelennamine citrate; alkylamines, such aschlorpheniramine and acrivastine; piperazines, such as hydroxyzinehydrochloride, hydroxyzine pamoate, cyclizine hydrochloride, cyclizinelactate, meclizine hydrochloride and cetirizine hydrochloride;piperidines, such as astemizole, levocabastine hydrochloride, loratadineor its descarboethoxy analogue, terfenadine and fexofenadinehydrochloride; azelastine hydrochloride; and the like, or apharmaceutically acceptable salt thereof; or, for those compounds listedas a salt, alternate pharmaceutically acceptable salt thereof.

Unless otherwise indicated, exemplary suitable doses for the othertherapeutic agents administered in combination with a compound of theinvention are in the range of about 0.05 μg/day to about 100 mg/day.

The following formulations illustrate representative compositions of theinvention, as well as exemplary methods of preparation. One or moresecondary agents can optionally be formulated with the compound of theinvention (primary active agent). Alternately, the secondary agents(s)can be formulated separately and co-administered with the primary activeagent, either simultaneously or sequentially. For example, in oneembodiment, a single dry powder formulation can be manufactured toinclude both the compound of the invention and one or more secondaryagents. In another embodiment, one formulation is manufactured tocontain the compound of the invention and separate formulation(s) aremanufactured to contain the secondary agent(s). Such dry powderformulations can then be packaged in separate blister packs andadministered with a single DPI device.

Exemplary Dry Powder Formulation for Administration by Inhalation

0.2 mg of a compound of the invention is micronized and then blendedwith 25 mg of lactose. The blended mixture is then loaded into a gelatininhalation cartridge. The contents of the cartridge are administeredusing a powder inhaler.

Exemplary Dry Powder Formulation for Administration by a Dry PowderInhaler

A dry powder is prepared having a bulk formulation ratio of micronizedcompound of the invention (active agent) to lactose of 1:200. The powderis packed into a dry powder inhalation device capable of deliveringbetween about 10 μg and 100 μg of active agent per dose.

Exemplary Formulations for Administration by a Metered Dose Inhaler

A suspension containing 5 wt % of a compound of the invention (activeagent) and 0.1 wt % lecithin is prepared by dispersing 10 g of theactive agent as micronized particles with a mean size less than 10 μm ina solution formed from 0.2 g of lecithin dissolved in 200 mL ofdemineralized water. The suspension is spray dried and the resultingmaterial is micronized to particles having a mean diameter less than 1.5μm. The particles are loaded into cartridges with pressurized1,1,1,2-tetrafluoroethane.

Alternately, a suspension containing 5 wt % of the active agent, 0.5 wt% lecithin, and 0.5 wt % trehalose is prepared by dispersing 5 g of theactive agent as micronized particles with a mean size less than 10 μm ina colloidal solution formed from 0.5 g of trehalose and 0.5 g oflecithin dissolved in 100 mL of demineralized water. The suspension isspray dried and the resulting material is micronized to particles havinga mean diameter less than 1.5 μm. The particles are loaded intocanisters with pressurized 1,1,1,2-tetrafluoroethane.

Exemplary Aqueous Aerosol Formulation for Administration by Nebulizer

A pharmaceutical composition is prepared by dissolving 0.5 mg of acompound of the invention (active agent) in 1 mL of a 0.9% sodiumchloride solution acidified with citric acid. The mixture is stirred andsonicated until the active agent is dissolved. The pH of the solution isadjusted to a value in the range of from 3 to 8 (typically about 5) bythe slow addition of NaOH.

Exemplary Hard Gelatin Capsule Formulation for Oral Administration

The following ingredients are thoroughly blended and then loaded into ahard gelatin capsule: 250 mg of a compound of the invention, 200 mg oflactose (spray-dried), and 10 mg of magnesium stearate, for a total of460 mg of composition per capsule.

Exemplary Suspension Formulation for Oral Administration

The following ingredients are mixed to form a suspension containing 100mg of active ingredient per 10 mL of suspension.

Ingredients Amount Compound of the invention 1.0 g Fumaric acid 0.5 gSodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 gGranulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum k(Vanderbilt Co.) 1.0 g Flavoring 0.035 mL Colorings 0.5 mg Distilledwater q.s. to 100 mL

Exemplary Injectable Formulation

The following ingredients are blended and the pH is adjusted to 4±0.5using 0.5 N HCl or 0.5 N NaOH.

Ingredients Amount Compound of the invention 0.2 g Sodium acetate buffersolution (0.4 M) 2.0 mL HCl (0.5 N) or NaOH (0.5 N) q.s. to pH 4 Water(distilled, sterile) q.s. to 20 mL

Utility

The compounds of the invention are expected to be useful as muscarinicreceptor antagonists and therefore, are expected to be useful fortreating medical conditions mediated by muscarinic receptors, i.e.,medical conditions which are ameliorated by treatment with a muscarinicreceptor antagonist. These medical conditions include, by way ofexample, pulmonary disorders or diseases including those associated withreversible airway obstruction, such as chronic obstructive pulmonarydisease (e.g., chronic and wheezy bronchitis and emphysema), asthma,pulmonary fibrosis, allergic rhinitis, rhinorrhea, and the like. Othermedical conditions that can be treated with muscarinic receptorantagonists are genitourinary tract disorders, such as overactivebladder or detrusor hyperactivity and their symptoms; gastrointestinaltract disorders, such as irritable bowel syndrome, diverticular disease,achalasia, gastrointestinal hypermotility disorders and diarrhea;cardiac arrhythmias, such as sinus bradycardia; Parkinson's disease;cognitive disorders, such as Alzheimer's disease; dismenorrhea; and thelike.

In one embodiment, the compounds of the invention are useful fortreating smooth muscle disorders in mammals, including humans and theircompanion animals (e.g., dogs, cats etc.). Smooth muscle disordersinclude, by way of illustration, overactive bladder, chronic obstructivepulmonary disease and irritable bowel syndrome. When used to treatsmooth muscle disorders or other conditions mediated by muscarinicreceptors, the compounds of the invention will typically be administeredorally, rectally, parenterally or by inhalation in a single daily doseor in multiple doses per day. The amount of active agent administeredper dose or the total amount administered per day will typically bedetermined by the patient's physician and will depend on factors such asthe nature and severity of the patients condition, the condition beingtreated, age and general health of the patient, tolerance of the patientto the active agent, route of administration and the like.

Typically, suitable doses for treating smooth muscle disorders or otherdisorders mediated by muscarinic receptors will range from about 0.14μg/kg/day to about 7 mg/kg/day of active agent; including from about0.15 μg/kg/day to about 5 mg/kg/day. For an average 70 kg human, thiswould amount to about 10 μg per day to about 500 mg per day of activeagent.

In a specific embodiment, the compounds of the invention are useful fortreating pulmonary or respiratory disorders, such as COPD or asthma, inmammals including humans. When used to treat such disorders, thecompounds of the invention will typically be administered by inhalationin multiple doses per day, in a single daily dose or a single weeklydose. Generally, the dose for treating a pulmonary disorder will rangefrom about 10-200 μg/day. As used herein, COPD includes chronicobstructive bronchitis and emphysema (see, for example, Barnes, ChronicObstructive Pulmonary Disease, N Engl J Med 343:269-78 (2000)). Whenused to treat a pulmonary disorder, the compounds of the invention areoptionally administered in combination with other therapeutic agentssuch as a β₂-adrenoreceptor agonist; a corticosteroid, a non-steroidalanti-inflammatory agent, or combinations thereof.

When administered by inhalation, the compounds of the inventiontypically have the effect of producing bronchodilation. Accordingly, inanother embodiment, the invention is directed to a method of producingbronchodilation in a patient, the method comprising administering to apatient a bronchodilation-producing amount of a compound of theinvention. Generally, the therapeutically effective dose for producingbronchodilation will range from about 10-200 μg/day.

In another embodiment, the compounds of the invention are used to treatoveractive bladder. When used to treat overactive bladder, the compoundsof the invention will typically be administered orally in a single dailydose or in multiple doses per day; preferably in a single daily dose.Preferably, the dose for treating overactive bladder will range fromabout 1.0-500 mg/day.

In yet another embodiment, the compounds of the invention are used totreat irritable bowel syndrome. When used to treat irritable bowelsyndrome, the compounds of the invention will typically be administeredorally or rectally in a single daily dose or in multiple doses per day.Preferably, the dose for treating irritable bowel syndrome will rangefrom about 1.0-500 mg/day.

Since compounds of the invention are muscarinic receptor antagonists,such compounds are also useful as research tools for investigating orstudying biological systems or samples having muscarinic receptors. Suchbiological systems or samples may comprise M₁, M₂, M₃, M₄ and/or M₅muscarinic receptors. Any suitable biological system or sample havingmuscarinic receptors may be employed in such studies which may beconducted either in vitro or in vivo. Representative biological systemsor samples suitable for such studies include, but are not limited to,cells, cellular extracts, plasma membranes, tissue samples, mammals(such as mice, rats, guinea pigs, rabbits, dogs, pigs, etc.), and thelike. In one embodiment, a biological assay is conducted by contacting abiological system or sample (comprising a muscarinic receptor) with amuscarinic receptor-antagonizing amount of a compound of the invention.The effects of antagonizing the muscarinic receptor are then determinedusing conventional procedures and equipment, such as radioligand bindingassays and functional assays. Such functional assays includeligand-mediated changes in intracellular cyclic adenosine monophosphate(cAMP), ligand-mediated changes in activity of the enzyme adenylylcyclase (which synthesizes cAMP), ligand-mediated changes inincorporation of guanosine 5′-O-(γ-thio)triphosphate ([³⁵S]GTPγS) intoisolated membranes via receptor catalyzed exchange of [³⁵S]GTPγS forGDP, ligand-mediated changes in free intracellular calcium ions(measured, for example, with a fluorescence-linked imaging plate readeror FLIPR® from Molecular Devices, Inc.). A compound of the inventionwill antagonize or decrease the activation of muscarinic receptors inany of the functional assays listed above, or assays of a similarnature. A muscarinic receptor-antagonizing amount of a compound of theinvention will typically range from about 0.1-100 nanomolar.

Additionally, the compounds of the invention can be used as researchtools for discovering and evaluating new compounds that have muscarinicreceptor antagonist activity. In one embodiment, a method of evaluatinga test compound in a biological assay, comprises: (a) conducting abiological assay with a test compound to provide a first assay value;(b) conducting the biological assay with a compound of formula I toprovide a second assay value; wherein step (a) is conducted eitherbefore, after or concurrently with step (b); and (c) comparing the firstassay value from step (a) with the second assay value from step (b).Exemplary biological assays include, by way of illustration and notlimitation, a muscarinic receptor binding assay or a bronchoprotectionassay in a mammal. For example, muscarinic receptor binding data (e.g.,as determined by in vitro radioligand displacement assays) for a testcompound or a group of test compounds can be compared to the muscarinicreceptor binding data for a compound of the invention to identify thosetest compounds that have about equal or superior muscarinic receptorbinding, if any. This aspect of the invention includes, as separateembodiments, both the generation of comparison data (using theappropriate assays) and the analysis of the test data to identify testcompounds of interest.

In another embodiment, the compounds of the invention are used toantagonize a muscarinic receptor in a biological system, and a mammal inparticular, such as mice, rats, guinea pigs, rabbits, dogs, pigs, humansand so forth. A therapeutically effective amount of a compound offormula I is administered to the mammal, and the effects of antagonizingthe muscarinic receptor can then determined using conventionalprocedures and equipment, examples of which are described above.

Among other properties, compounds of formula I have been found to bepotent inhibitors of M₃ muscarinic receptor activity. Accordingly, in aspecific embodiment, the invention is directed to those compounds havingan inhibition dissociation constant (Ks) for the M₃ receptor subtype ofless than or equal to 10 nM; preferably, less than or equal to 5 nM; (asdetermined, for example, by an in vitro radioligand displacement assay).Additionally, compounds of formula I are expected to possess a desirableduration of action. Accordingly, in another specific embodiment, theinvention is directed to those compounds having a duration of actiongreater than or equal to about 24 hours. Moreover, compounds of theinvention are also expected to possess reduced side effects, such as drymouth, at efficacious doses when administered by inhalation compared toother known muscarinic receptor antagonists administered by inhalation(such as tiotropium).

These properties, as well as the utility of the compounds of theinvention, can be demonstrated using various in vitro and in vivo assayswell-known to those skilled in the art. For example, representativeassays are described in further detail in the following Examples.

EXAMPLES

The following Preparations and Examples illustrate specific embodimentsof the invention. In these examples, the following abbreviations havethe following meanings:

-   -   AC adenylyl cyclase    -   ACh acetylcholine    -   ACN acetonitrile    -   BOC tert-butoxycarbonyl    -   BSA bovine serum albumin    -   cAMP 3′-5′ cyclic adenosine monophosphate    -   CHO Chinese hamster ovary    -   cM₅ cloned chimpanzee M₅ receptor    -   DCM dichloromethane (i.e., methylene chloride)    -   DIPEA N,N-diisopropylethylamine    -   DMSO dimethyl sulfoxide    -   dPBS Dulbecco's phosphate buffered saline    -   DMAP 4-dimethylaminopyridine    -   DMF dimethylformamide    -   DMSO dimethyl sulfoxide    -   EDCI-ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride    -   EtOAc ethyl acetate    -   EtOH ethanol    -   FBS fetal bovine serum    -   FLIPR fluorometric imaging plate reader    -   HATU O-(7-azabenzotriazol-1-yl-N,N,N′N′-tetramethyluronium        hexafluorophosphate    -   HBSS Hank's buffered salt solution    -   HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid    -   HOAt 1-hydroxy-7-azabenzotriazole    -   hM₁ cloned human M₁ receptor    -   hM₂ cloned human M₂ receptor    -   hM₃ cloned human M₃ receptor    -   hM₄ cloned human M₄ receptor    -   hM₅ cloned human M₅ receptor    -   HOAc acetic acid    -   HOAt 1-hydroxy-7-azabenzotriazole    -   HOBT 1-hydroxybenzotriazole hydrate    -   HPLC high-performance liquid chromatography    -   IPA isopropanol    -   MCh methylcholine    -   MeCN methylcyanide    -   MeOH methanol    -   NaBH(OAc)₃ sodium triacetoxyborohydride    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran        Any other abbreviations used herein but not defined have their        standard, generally accepted meaning. Unless noted otherwise,        all materials, such as reagents, starting materials and        solvents, were purchased from commercial suppliers (such as        Sigma-Aldrich, Fluka, and the like) and were used without        further purification.

Unless otherwise indicated, HPLC analysis was conducted using an Agilent(Palo Alto, Calif.) Series 1100 instrument equipped with a Zorbax BonusRP 2.1×50 mm column (Agilent) having a 3.5 micron particle size.Detection was by UV absorbance at 214 nm. The mobile phases employedwere as follows (by volume): A is ACN (2%), water (98%) and TFA (0.1%);and B is ACN (90%), water (10%) and TFA (0.1%). HPLC 10-70 data wasobtained using a flow rate of 0.5 mL/minute of 10 to 70% B over a 6minute gradient (with the remainder being A). Similarly, HPLC 5-35 dataand HPLC 10-90 data were obtained using 5 to 35% B; or 10 to 90% B overa 5 minute gradient.

Liquid chromatography mass spectrometry (LCMS) data were obtained withan Applied Biosystems (Foster City, Calif.) Model API-150EX instrument.LCMS 10-90 data was obtained using 10 to 90% Mobile Phase B over a 5minute gradient. Small-scale purification was conducted using anAPI-150EX Prep Workstation system from Applied Biosystems. The mobilephases employed were as follows (by volume): A is water and 0.05% TFA;and B is ACN and 0.05% TFA. For arrays (typically about 3 to 50 mgrecovered sample size) the following conditions were used: 20 mL/minflow rate; 15 minute gradients and a 20 mm×50 mm Prism RP column with 5micron particles (Thermo Hypersil-Keystone, Bellefonte, Pa.). For largerscale purifications (typically greater than 100 mg crude sample), thefollowing conditions were used: 60 mL/min flow rate; 30 minute gradientsand a 41.4 mm×250 mm Microsorb BDS column with 10 micron particles(Varian, Palo Alto, Calif.).

Preparation 1 Biphenyl-2-ylcarbamic Acid Piperidin-4-yl Ester

Biphenyl-2-isocyanate (97.5 g, 521 mmol) and4-hydroxy-N-benzylpiperidine (105 g, 549 mmol) were heated together at70° C. for 12 hours. The reaction mixture was then cooled to 50° C. andEtOH (1 L) was added and then 6M HCl (191 mL) was added slowly. Theresulting mixture was then cooled to ambient temperature and ammoniumformate (98.5 g, 1.56 mol) was added and then nitrogen gas was bubbledthrough the solution vigorously for 20 minutes. Palladium on activatedcarbon (20 g, 10 wt % dry basis) was then added and the reaction mixturewas heated at 40° C. for 12 hours, and then filtered through a pad ofCelite. The solvent was then removed under reduced pressure and 1M HCl(40 mL) was added to the crude residue. The pH of the mixture was thenadjusted with 10 N NaOH to pH 12. The aqueous layer was extracted withEtOAc (2×150 mL) and the organic layer was dried over MgSO₄, filteredand the solvent removed under reduced pressure to give 155 g of thetitle intermediate (100% yield). HPLC (10-70) R_(t)=2.52; m/z: [M+H⁺]calcd for C₁₈H₂₀N₂O₂, 297.15; found, 297.3.

Preparation 2 N-Benzyl-N-methylaminoacetaldehyde

To a 3-necked 2-L flask was added N-benzyl-N-methylethanolamine (30.5 g,0.182 mol), DCM (0.5 L), DIPEA (95 mL, 0.546 mol) and DMSO (41 mL, 0.728mol). Using an ice bath, the mixture was cooled to about −10° C. andsulfur trioxide pyridine-complex (87 g, 0.546 mol) was added in 4portions over 5 minute intervals. The reaction was stirred at −10° C.for 2 hours. Before removing the ice-bath, the reaction was quenched byadding water (0.5 L). The aqueous layer was separated and the organiclayer was washed with water (0.5 L) and brine (0.5 L) and then driedover MgSO₄ and filtered to provide the title compound which was usedwithout further purification.

Preparation 3 Biphenyl-2-ylcarbamic Acid1-[2-(Benzylmethylamino)ethyl]piperidin-4-yl Ester

To a 2-L flask, containing N-benzyl-N-methylaminoacetaldehyde (19.8 g,0.121 mol; prepared as described in Preparation 2) in DCM (0.5 L) wasadded biphenyl-2-ylcarbamic acid piperidin-4-yl ester (30 g, 0.101 mol;prepared as described in Preparation 1) followed by NaBH(OAc)₃ (45 g,0.202 mol). The reaction mixture was stirred overnight and then quenchedby the addition of 1 N HCl (0.5 L) with vigorous stirring. Three layerswere observed and the aqueous layer was removed. After washing with 1NNaOH (0.5 L), a homogenous organic layer was obtained which was thenwashed with a saturated solution of aqueous NaCl (0.5 L), dried overMgSO₄, filtered and the solvent removed under reduced pressure. Theresidue was purified by dissolving it in a minimal amount of IPA andcooling this solution to 0° C. to form a solid which was collected andwashed with cool IPA to provide 42.6 g of the title intermediate (95%yield). MS m/z: [M+H⁺] calcd f for C₂₈H₃₃N₃O₂, 444.3; found, 444.6.R_(f)=3.51 min (10-70 ACN: H₂O, reverse phase HPLC).

Preparation 3A Biphenyl-2-ylcarbamic Acid1-[2-(Benzylmethylamino)ethyl]piperidin-4-yl Ester

The title compound was prepared by mesylation of N-benzyl-N-methylethanolamine, which was then reacted with biphenyl-2-ylcarbamic acidpiperidin-4-yl ester in an alkylation reaction.

A 500 mL flask (reactor flask) was charged withN-benzyl-N-methylethanolamine (24.5 mL), DCM (120 mL), NaOH (80 mL; 30wt %) and tetrabutylammonium chloride. Mixing at low speed throughoutthe reaction, the mixture was cooled to −10° C. (cooling bath), and theaddition funnel charged with DCM (30 mL) and mesyl chloride (15.85 mL),which was added drop wise at a constant rate over 30 minutes. Theaddition was exothermic, and stirring was continued for 15 minutes whilethe temperature equilibrated back to −10° C. The reaction was held forat least 10 minutes to ensure full hydrolysis of the excess mesylchloride.

A 250 mL flask was charged with biphenyl-2-ylcarbamic acidpiperidin-4-yl ester (26 g; prepared as described in Preparation 1) andDCM (125 mL), stirred for 15 minutes at room temperature, and themixture chilled briefly to 10° C. to form a slurry. The slurry was thencharged into the reactor flask via the addition funnel. The cooling bathwas removed and the reaction mixture was warmed to 5° C. The mixture wastransferred to a separatory funnel, the layers allowed to settle, andthe aqueous layer removed. The organic layer was transferred back to thereactor flask, stirring resumed, the mixture held to room temperature,and the reaction monitored by HPLC for a total of 3.5 hours.

The reactor flask was charged with NaOH (1M solution; 100 mL), stirred,and the layers allowed to settle. The organic layer was separated,washed (NaCl satd. solution), its volume partially reduced under vacuum,and subjected to repeated IPA washings. The solids were collected andallowed to air-dry (25.85 g, 98% purity). Additional solids wereobtained from further processing of the mother liquor (volume reduction,IPA, cooling).

Preparation 4 Biphenyl-2-ylcarbamic Acid1-(2-Methylaminoethyl)piperidin-4-yl Ester

To a Parr hydrogenation flask was added biphenyl-2-ylcarbamic acid1-[2-(benzylmethylamino)ethyl]piperidin-4-yl ester (40 g, 0.09 mol;prepared as described in Preparation 3) and EtOH (0.5 L). The flask wasflushed with nitrogen gas and palladium on activated carbon (15 g, 10wt. % (dry basis), 37% wt/wt) was added along with HOAc (20 mL). Themixture was kept on the Parr hydrogenator under a hydrogen atmosphere(˜50 psi) for 3 hours. The mixture was then filtered and washed withEtOH. The filtrate was condensed and the residue was dissolved in aminimal amount of DCM. Isopropyl acetate (10 volumes) was added slowlyto form a solid which was collected to provide 22.0 g of the titleintermediate (70% yield). MS m/z: [M+H⁺] calcd for C₂₁H₂₇N₃O₂, 354.2;found, 354.3. R_(f)=2.96 min (10-70 ACN: H₂O, reverse phase HPLC).

Preparation 5 Biphenyl-2-ylcarbamic Acid1-{2-[(4-Formylbenzoyl)methylamino]ethyl}piperidin-4-yl Ester

To a three-necked 1-L flask was added 4-carboxybenzaldehyde (4.77 g,31.8 mmol), EDC (6.64 g, 34.7 mmol), HOBT (1.91 g, 31.8 mmol), and DCM(200 mL). When the mixture was homogenous, a solution ofbiphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester(10 g, 31.8 mmol; prepared as described in Preparation 4) in DCM (100mL) was added slowly. The reaction mixture was stirred at roomtemperature for 16 hours and then washed with water (1×100 mL), 1N HCl(5×60 mL), 1N NaOH (1×100 mL), brine (1×50 mL), dried over sodiumsulfate, filtered and concentrated to afford 12.6 g of the titleintermediate (92% yield; 85% purity based on HPLC). MS m/z: [M+H⁺] calcdfor C₂₉H₃₁N₃O₄, 486.2; found, 486.4. R_(f) 3.12 min (10-70 ACN: H₂O,reverse phase HPLC).

Example 1

To a stirred solution of biphenyl-2-ylcarbamic acid1-{2-[(4-formylbenzoyl) methylamino]ethyl}piperidin-4-yl ester (50 mg,0.1 mmol; prepared as described in Preparation 5) in MeOH (1 mL) wasadded 1-acetylpiperazine (26 mg, 0.2 mmol). The mixture was shake for anhour and NaBH(OAc)₃ (67 mg, 0.3 mmol) was added. This was allowed tostir for 14 hours. The solvent was then removed under reduced pressure.To the mixture was added 1:1 HOAc:H₂O (1.0 mL) and then purified byreverse phase HPLC (gradient elution, ACN/H₂O) to provide 37.8 mg ofCompound 1-1 with 99% purity.

Compounds 1-2 to 1-44 were made in a similar manner by substituting theappropriate amine in the reductive amination step.

# Name —NR⁶R⁷ 1-1 biphenyl-2-yl-carbamic acid1-(2-{[4-(4-acetylpiperazin- 1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₅H₄₃N₅O₄, 598.33;found, 598.4.

1-2 biphenyl-2-ylcarbamic acid 1-{2-[(4-aminomethyl —NH₂benzoyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₂₉H₃₄N₄O₃, 487.26; found, 487.3, 509.3. 1-3 biphenyl-2-ylcarbamicacid 1-{2-[(4-{[(furan-2-carbonyl)amino]methyl}benzoyl)methylamino]ethyl} piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₄H₃₆N₄O₅, 581.27; found, 581.2.

1-4 biphenyl-2-ylcarbamic acid 1-(2-{[4-(acetylaminomethyl)benzoyl]methylamino}ethyl) piperidin-4-yl ester. MS m/z: [M + H⁺]calcd for C₃₁H₃₆N₄O₄, 529.27; found, 529.2.

1-5 biphenyl-2-ylcarbamic acid 1-{2-[methyl-(4-{[(pyridine-4-carbonyl)amino]methyl}benzoyl)amino]ethyl} piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₅H₃₇N₅O₄, 592.28; found, 592.2.

1-6 biphenyl-2-ylcarbamic acid 1-[2-({4-[(cyclopropanecarbonylamino)methyl]benzoyl}methylamino)ethyl] piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₃H₃₈N₄O₄, 555.29; found, 555.3.

1-7 biphenyl-2-ylcarbamic acid 1-{2-[methyl-(4-{[(thiophene-2-carbonyl)amino]methyl}benzoyl) amino]ethyl}piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₄H₃₆N₄O₄S, 597.25; found, 597.2.

1-8 biphenyl-2-ylcarbamic acid 1-[2-({4-[(cyclobutanecarbonylamino)methyl]benzoyl}methylamino)ethyl] piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₄H₄₀N₄O₄, 569.31; found, 569.3.

1-9 biphenyl-2-ylcarbamic acid 1-(2-{[4-(isopropylaminomethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺]calcd for C₃₂H₄₀N₄O₃, 529.31; found, 529.3.

1-10 biphenyl-2-ylcarbamic acid 1-[2-({4-[(cyclopropylmethylamino)methyl]benzoyl}methylamino)ethyl] piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₃H₄₀N₄O₃, 541.31; found, 541.3.

1-11 biphenyl-2-ylcarbamic acid 1-{2-[methyl-(4-morpholin-4-ylmethylbenzoyl)amino]ethyl}piperidin-4-yl ester. MS m/z: [M + H ⁺]calcd for C₃₃H₄₀N₄O₄, 557.31; found, 557.2.

1-12 biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(2-methanesulfonylethyl)methylamino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₃H₄₂N₄O₅S, 607.29; found, 607.2.

1-13 biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-ethylpiperazin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₅H₄₅N₅O₃, 584.35; found, 584.3.

1-14 biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-isopropylpiperazin-1-ylmethyl)benzoyl]methylamino} ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₆H₄₇N₅O₃, 598.37; found, 598.3.

1-15 biphenyl-2-ylcarbamic acid 1-[2-({4-[(ethylisopropylamino)methyl]benzoyl}methylamino) ethyl]piperidin-4- yl ester. MS m/z:[M + H⁺] calcd for C₃₄H₄₄N₄O₃, 557.34; found, 557.3.

1-16 biphenyl-2-ylcarbamic acid 1-(2-{[4-(2,6-dimethylmorpholin-4-ylmethyl)benzoyl]methylamino}ethyl) piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₅H₄₄N₄O₄, 585.34; found, 585.3.

1-17 biphenyl-2-ylcarbamic acid 1-{2-[(4-{[bis-(2- —N[(CH₂)₂OH]₂hydroxyethyl)amino]methyl}benzoyl)methylamino] ethyl}piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₃H₄₂N₄O₅, 575.32; found, 575.3. 1-18biphenyl-2-ylcarbamic acid 1-(2-{[4-(tert-butylaminomethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺]calcd for C₃₃H₄₂N₄O₃, 543.33; found, 543.3.

1-19 biphenyl-2-ylcarbamic acid 1-[2-({4-[(ethylmethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4- yl ester. MS m/z:[M + H⁺] calcd for C₃₂H₄₀N₄O₃, 529.31; found, 529.2.

1-20 biphenyl-2-ylcarbamic acid 1-{2-[(4-{[bis-(2-ethoxyethyl)amino]methyl}benzoyl)methylamino]ethyl} piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₇H₅₀N₄O₅, 631.38; found, 631.3.

1-21 biphenyl-2-ylcarbamic acid 1-[2-(methyl-{4-[(methylpyridin-3-ylmethylamino)methyl]benzoyl}amino) ethyl]piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₆H₄₁N₅O₃, 592.32; found, 592.3.

1-22 biphenyl-2-ylcarbamic acid 1-{2-[(4-{[bis(2-methoxyethyl)amino]methyl}benzoyl)methylamino]ethyl} piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₅H₄₆N₄O₅, 603.35;_found, 603.3.

1-23 biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(2-hydroxyethyl)methylamino]methyl}benzoyl)methylamino]ethyl} piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₂H₄₀N₄O₄, 545.31; found, 545.2.

1-24 biphenyl-2-ylcarbamic acid 1-[2-(methyl-{4-[(methyl-pyridin-4-ylmethylamino)methyl]benzoyl}amino) ethyl]piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₆H₄₁N₅O₃, 592.32; found, 592.3.

1-25 biphenyl-2-ylcarbamic acid 1-[2-({4-[4-(2-methoxyethyl)piperazin-1-ylmethyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₆H₄₇N₅O₄, 614.36; found, 614.3.

1-26 biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-ethanesulfonylpiperazin-1-ylmethyl)benzoyl]methylamino}ethyl) piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₅H₄₅N₅O₅S, 648.31; found, 648.3.

1-27 biphenyl-2-ylcarbamic acid 1-(2-{[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)benzoyl]methylamino}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₄H₄₁N₅O₃, 568.33; found, 568.4.

1-28 biphenyl-2-ylcarbamic acid 1-[2-({4-[(2-hydroxyethyl —NH[(CH₂)₂OH]amino)methyl]benzoyl}methylamino)ethyl]piperidin-4- yl ester. MS m/z:[M + H⁺] calcd for C₃₁H₃₈N₄O₄, 531.29; found, 531.2. 1-29biphenyl-2-ylcarbamic acid 1-(2-{methyl-[4-(4-pyridin-4-ylpiperazin-1-ylmethyl)benzoyl]amino}ethyl piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₈H₄₄N₆O₃, 633.35; found, 633.4.

1-30 biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-dimethylcarbamoylmethylpiperazin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₇H₄₈N₆O₄, 641.37; found, 641.4.

1-31 biphenyl-2-ylcarbamic acid 1-(2-{methyl-[4-(4-pyridin-4-ylmethylpiperazin-1-ylmethyl)benzoyl]amino} ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₉H₄₆N₆O₃, 647.36; found, 647.4.

1-32 biphenyl-2-ylcarbamic acid 1-[2-(methyl-{4-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-ylmethyl]benzoyl}amino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₉H₅₀N₆O₄,667.39; found, 667.4.

1-33 biphenyl-2-ylcarbamic acid 1-[2-({4-[(2-hydroxyethyl —NH(CH₃)amino)methyl]benzoyl}methylamino)ethyl]piperidin-4- yl ester. MS m/z:[M + H⁺] calcd for C₃₀H₃₆N₄O₃, 501.29; found, 501.2. 1-34biphenyl-2-ylcarbamic acid 1-{2-[(4-ethylaminomethyl —NH(CH₂CH₃)benzoyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₁H₃₈N₄O₃, 515.29; found, 515.2. 1-35 biphenyl-2-ylcarbamic acid1-{2-[(4-cyclopropylamino methylbenzoyl)methylamino]ethyl}piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₂H₃₈N₄O₃, 527.29; found, 527.2.

1-36 biphenyl-2-ylcarbamic acid 1-[2-({4-[(2-methoxyethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4- yl ester. MS m/z:[M + H⁺] calcd for C₃₂H₄₀N₄O₄, 545.31; found, 545.2.

1-37 biphenyl-2-ylcarbamic acid 1-(2-{methyl-[4-(3-oxopiperazin-1-ylmethyl)benzoyl]amino}ethyl) piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₃H₃₉N₅O₄, 570.30; found, 570.2.

1-38 biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-acetyl-[1,4]diazepan-1-ylmethyl)benzoyl]methylamino}ethyl) piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₆H₄₅N₅O₄, 612.35; found, 612.4.

1-39 biphenyl-2-ylcarbamic acid 1-[2-({4-[4-(4-hydroxyphenyl)piperazin-1-ylmethyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₉H₄₅N₅O₄, 648.35; found, 648.4.

1-40 biphenyl-2-ylcarbamic acid 1-[2-({4-[(carbamoylmethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4- yl ester. MS m/z:[M + H⁺] calcd for C₃₁H₃₇N₅O₄, 544.28; found, 544.2.

1-41 biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-dimethylcarbamoylpiperazin-1-ylmethyl)benzoyl]methylamino} ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₆H₄₆N₆O₄, 627.36; found, 627.4.

1-42 biphenyl-2-ylcarbamic acid 1-[2-(methyl-{4-[4-(pyrrolidine-1-carbonyl)piperazin-1-ylmethyl]benzoyl}amino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₈H₄₈N₆O₄,653.37; found, 653.4.

1-43 biphenyl-2-ylcarbamic acid 1-[2-(methyl-{4-[4-(piperidine-1-carbonyl)piperazin-1-ylmethyl]benzoyl}amino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₉H₅₀N₆O₄,667.39; found, 667.4.

1-44 biphenyl-2-ylcarbamic acid 1-[2-(methyl-{4-[4-(morpholine-4-carbonyl)piperazin-1-ylmethyl]benzoyl}amino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₈H₄₈N₆O₅,669.37; found, 669.4.

Preparation 6

To a stirred solution of biphenyl-2-ylcarbamic acid piperidin-4-yl ester(2.00 g, 6.76 mmol; prepared as described in Preparation 1) and DIPEA(3.54 mL, 20.3 mmol) in MeCN (67.6 mL) at 50° C., was added 2-BOC-aminoethyl bromide (1.82 g, 8.11 mmol) and the reaction mixture was heated at50° C. overnight. The solvent was removed under reduced pressure anddissolved in DCM (60 mL) and washed with saturated aqueous sodiumbicarbonate solution (30 mL), organics dried (MgSO₄) and solvent removedunder reduced pressure. The crude residue was purified by columnchromatography (5% MeOH/DCM) to give the title intermediate as a whitesolid (2.32 g, 78%).

Preparation 7 Biphenyl-2-ylcarbamic acid 1-(2-aminoethyl)piperidin-4-ylester

The product of Preparation 6 was dissolved in TFA/DCM (25%, 52 mL) andstirred at room temperature for 2 hours. The solvent was removed underreduced pressure and the crude residue dissolved in DCM (30 mL) andwashed with 1N NaOH (15 mL). The organics were separated, dried (MgSO₄)and solvent removed under reduced pressure to give the titleintermediate (1.61 g, 90%).

Preparation 8

To a stirred solution of the product of Preparation 7 (339 mg, 1 mmol),BOC-(4-aminomethyl)benzoic acid (301 mg, 1.2 mmol) and HATU (456 mg, 1.2mmol) in DMF (2 mL), was added DIPEA (226 μL, 1.3 mmol). The reactionmixture was stirred at room temperature overnight before removing thesolvent under reduced pressure. The resulting residue was dissolved inDCM (20 mL) and washed with saturated aqueous sodium bicarbonatesolution (10 mL), organics dried (MgSO₄) and solvent removed underreduced pressure to yield the crude title intermediate, which was useddirectly in the next step.

Preparation 9 Biphenyl-2-ylcarbamic Acid1-[2-(4-Formylbenzoylamino)ethyl]piperidin-4-yl Ester

A mixture of 4-carboxybenzaldehyde (0.95 g, 6.35 mmol) and HATU (3.02 g,7.94 mmol) in 55 mL of DCM was stirred at room temperature for 1 hourand then biphenyl-2-ylcarbamic acid 1-(2-aminoethyl)piperidin-4-yl ester(3 g, 5.29 mmol; prepared as described in Preparation 7) and DIPEA (4.6mL, 26.45 mmol) were added. The resulting mixture was stirred at roomtemperature for 2 hours and then diluted with 100 mL of DCM and washedwith saturated sodium bicarbonate (150 mL) and brine (150 mL). Theorganic layer was dried over MgSO₄, filtered and concentrated to provide2.3 g of the title intermediate (92% yield), which was suitable for usewithout further purification.

Example 2

The crude product of Preparation 8 was dissolved in TFA/DCM (25%, 10 mL)and stirred at room temperature for 2 hours. The solvent was removedunder reduced pressure and crude residue dissolved in DCM (15 mL) andwashed with 5N NaOH (5 mL). The organics were separated, dried (MgSO₄)and solvent removed under reduced pressure to give Compound 2-1 (R⁶ andR⁷=H) (472 mg, ˜100% over 2 steps): biphenyl-2-ylcarbamic acid1-[2-(4-aminomethylbenzoyl amino)ethyl]piperidin-4-yl ester. MS m/z:[M+H⁺] calcd for C₂₈H₃₂N₄O₃, 473.25; found, 473.2.

Using the procedure of Example 1, but substituting the product ofPreparation 9 in place of the product of Preparation 5, and substitutingthe appropriate amine in the reductive amination step, compounds havingother R⁶ and R⁷ groups can also be made.

Preparation 10 3-[4-(Biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionicAcid Methyl Ester

Methyl 3-bromopropionate (553 μL, 5.07 mmol) was added to a stirredsolution of biphenyl-2-ylcarbamic acid piperidin-4-yl ester (1.00 g,3.38 mmol; prepared as described in Preparation 1) and DIPEA (1.76 mL,10.1 mmol) in ACN (34 mL) at 50° C. and the reaction mixture was heatedat 50° C. overnight. The solvent was then removed under reducedpressure, and the residue was dissolved in DCM (30 mL). The resultingsolution was washed with saturated aqueous sodium bicarbonate solution(10 mL), dried over MgSO₄, filtered and the solvent was removed underreduced pressure. The crude residue was purified by columnchromatography (5-10% MeOH/DCM) to give 905 mg of the title intermediate(70% yield).

Preparation 11 3-[4-(Biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionicAcid

A stirred solution of3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid methylester (902 mg, 2.37 mmol; prepared as described in Preparation 10) andlithium hydroxide (171 mg, 7.11 mmol) in 50% THF:H₂O (24 mL) was heatedat 30° C. overnight, and then acidified with concentrated HCl andlyophilized to give the title intermediate (˜100% yield, also containsLiCl salts).

Preparation 12 Biphenyl-2-ylcarbamic acid1-[2-(3-hydroxymethylbenzylcarbamoyl)ethyl]piperidin-4-yl Ester

To a stirred solution of3-[4-(Biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (0.5 g,1.36 mmol; prepared as described in Preparation 11) in DCM (200 mL) wasadded DIPEA (10.7 mL, 6.12 mmol), 3-aminomethylbenzyl alcohol (0.33 g,1.9 mmol), DMAP (0.14 g, 0.14 mmol) and EDCI (0.364 g, 1.9 mmol). Thereaction mixture was stirred at room temperature for 2 hours. Themixture was concentrated, taken up in EtOAc (20 mL) and then washed withK₂CO₃ (3×10 mL), H₂O (1×10 mL), brine (1×10 mL), dried over magnesiumsulfate, filtered and concentrated. The mixture was purified on silicagel (7% MeOH/CHCl₃) to afford 0.38 g of the title intermediate (57%yield).

Preparation 13 Biphenyl-2-ylcarbamic Acid1-[2-(3-formylbenzylcarbamoyl)ethyl]piperidin-4-yl Ester

To a flask was added biphenyl-2-ylcarbamic acid1-[2-(3-hydroxymethylbenzyl carbamoyl)ethyl]piperidin-4-yl ester (0.33g, 0.68 mmol; prepared as described in Preparation 12), DCM (5 mL),DIPEA (0.47 mL, 2.7 mol) and DMSO (0.2 mL, 2.7 mol). Using an ice bath,the mixture was cooled to about −10° C. and sulfur trioxidepyridine-complex (0.32 g, 2.0 mol) was added. The reaction was stirredat −10° C. for 0.75 hour. Before removing the ice-bath, the reaction wasquenched by adding water (5 mL). The aqueous layer was separated and theorganic layer was washed with water (2×5 mL), 1.0N NaHSO₄(aq) (2×5 mL),1.0N NaHCO₃(aq) (1×5 mL) and brine (0.5 L) and then dried over MgSO₄ andfiltered to provide the title compound which was used without furtherpurification.

Example 3

To a stirred solution of biphenyl-2-ylcarbamic acid 1-[2-(3-formylbenzylcarbamoyl)ethyl]piperidin-4-yl ester (39 mg, 0.08 mmol; prepared asdescribed in Preparation 13) in DCM (1 mL) was added2-benzyl-2,5-diaza-bicyclo[2.2.1]heptane (18.8 mg, 0.1 mmol), andNaBH(OAc)₃ (275 mg, 1.24 mmol). The mixture was stirred for 2 days andthen the solvent was removed under reduced pressure. A 1:1 solution ofHOAc and water (8.0 mL) was added to the reaction mixture. The mixturewas chromatographed on reverse-phase HPLC (gradient elution, 10-50%ACN/H₂O) to afford 4.0 mg of the title compound (5.6% yield) as abis(trifluoroacetate) salt.

Compounds 3-2 to 3-10 were made in a similar manner by substituting theappropriate amine in the reductive amination step.

# Name —NR⁶R⁷ 3-1 biphenyl-2-ylcarbamic acid 1-{2-[3-((1R,4R)-5-benzyl-2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)benzylcarbamoyl]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₄₁H₄₇N₅O₃, 658.37; found, 657.3.

3-2 biphenyl-2-ylcarbamic acid 1-[2-(3-aminomethylbenzyl —NH₂carbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₂₉H₃₄N₄O₃, 487.26; found, 487.4. 3-3 biphenyl-2-ylcarbamic acid1-[2-(3-{[(pyridin-4-ylmethyl)amino]methyl}benzylcarbamoyl)ethyl]piperidin- 4-yl ester. MS m/z:[M + H⁺] calcd for C₃₅H₃₉N₅O₃, 578.31; found, 578.2.

3-4 biphenyl-2-ylcarbamic acid 1-(2-{3-[(furan-2-ylmethylmethylamino)methyl]benzylcarbamoyl}ethyl) piperidin- 4-yl ester. MS m/z:[M + H⁺] calcd for C₃₅H₄₀N₄O₄, 581.31; found, 581.2.

3-5 {[3-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionylamino}methyl)benzyl]methylamino}acetic acid. MS m/z: [M + H⁺]calcd for C₃₂H₃₈N₄O₅, 559.28; found, 559.2.

3-6 biphenyl-2-ylcarbamic acid 1-[2-(3-cyclobutylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₃H₄₀N₄O₃, 541.31; found, 541.2.

3-7 biphenyl-2-ylcarbamic acid 1-[2-(3-cyclopropylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₂H₃₈N₄O₃, 527.29; found, 527.2.

3-8 biphenyl-2-ylcarbamic acid 1-[2-(3-morpholin-4-ylmethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₃H₄₀N₄O₄, 557.31; found, 557.2.

3-9 biphenyl-2-ylcarbamic acid 1-[2-(3-methylaminomethyl —NH(CH₃)benzylcarbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₀H₃₆N₄O₃, 501.28; found, 501.2.  3-10 biphenyl-2-ylcarbamic acid1-[2-(3-dimethylamino —N(CH₃)₂methylbenzylcarbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₁H₃₈N₄O₃, 515.29; found, 515.2.

Example 4

Using the procedure of Example 1, but substituting3-(4-formylphenyl)propionic acid in place of 4-carboxybenzaldehyde inPreparation 5, and substituting the appropriate amine in the reductiveamination step, the following compounds were prepared. The preparationof 3-(4-formylphenyl)propionic acid was done according to Tetrahedron52(20):6913-6930 (2001).

# Name —NR⁶R⁷ 4-1 biphenyl-2-ylcarbamic acid 1-(2-{methyl-[3- —NH(CH₃)(4-methyl aminomethylphenyl)propionyl]amino} ethyl)piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃ ₂H₄₀N₄O₃, 529.31; found, 529.2. 4-2biphenyl-2-ylcarbamic acid 1-(2-{[3-(4- —NH(CH₂CH₃) ethylaminomethylphenyl)propionyl] methylamino}ethyl)piperidin-4-yl ester. MS m/z:[M + H⁺] calcd for C₃ ₃H₄₂N₄O₃, 543.33; found, 543.2.

Preparation 14 Biphenyl-2-ylcarbamic Acid1-[2-(4-Aminomethylphenylcarbamoyl)ethyl]piperidin-4-yl Ester

To a stirred solution of 4-(N-tert-butoxycarbonylaminomethyl)aniline(756 mg, 3.4 mmol),3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionic acid (1.5 g,4.08 mmol; prepared as described in Preparation 11) and HATU (1.55 g,4.08 mmol) in DMF (6.8 mL), was added DIPEA (770 mL, 4.42 mmol). Thereaction mixture was stirred at 50° C. overnight, and then the solventwas removed under reduced pressure. The resulting residue was dissolvedin DCM (20 mL) and washed with saturated aqueous sodium bicarbonatesolution (10 mL). The organic phase was then dried over MgSO₄ and thesolvent was removed under reduced pressure. The crude product waspurified by flash chromatography (5-10% MeOH/DCM) to give a solid, whichwas dissolved in TFA/DCM (25%, 30 mL) and stirred at room temperaturefor 2 hours. The solvent was then removed under reduced pressure and thecrude residue was dissolved in DCM (30 mL) and washed with 1N NaOH (15mL). The organic phase was separated, dried over MgSO₄, filtered and thesolvent was removed under reduced pressure to give 1.5 g of the titleintermediate (94% yield over 2 steps).

Preparation 15 Biphenyl-2-ylcarbamic Acid1-[2-(4-Formylphenylcarbamoyl)ethyl]piperidin-4-yl Ester

A mixture of biphenyl-2-ylcarbamic acid1-[2-(4-aminomethylphenylcarbamoyl) ethyl]piperidin-4-yl ester (1 g, 2.7mmol; prepared as described in Preparation 14), 4-aminobenzyl alcohol(498 mg, 4.05 mmol), HATU (1.54 g, 4.05 mmol) and DIPEA (1.41 mL, 8.1mmol) in DCM (14 mL) was stirred at room temperature for 2 hours. Thereaction mixture was diluted with 100 mL of DCM and washed first with a1:3 mixture of 1N HCl/water (100 mL), then brine (100 mL). The organiclayer was dried over MgSO₄, filtered and concentrated. The residue wasdissolved in DCM (100 mL) and the solution was cooled to −5° C. DIPEA(1.1 mL, 6.33 mmol) and DMSO (1.5 mL, 21.1 mmol) were added to thesolution, followed by sulfur trioxide pyridine complex (1 g, 6.33 mmol).The reaction mixture was stirred at 0° C. for 1 hour then washed with asaturated solution of sodium bicarbonate (100 mL) and brine (100 mL).The organic layer was dried over MgSO₄, filtered and concentrated togive 0.84 g of the title intermediate (66% yield) as an oil.

Example 5

Using the procedure of Example 1, but substituting biphenyl-2-ylcarbamicacid 1-[2-(4-formylphenylcarbamoyl)ethyl]piperidin-4-yl ester (preparedas described in Preparation 15) in place of the product of Preparation5, and substituting the appropriate amine in the reductive aminationstep, the following compounds were prepared.

# Name —NR⁶R⁷ 5-1 biphenyl-2-ylcarbamic acid 1-[2-(4-aminomethylphenyl—NH₂ carbamoyl)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₂₈H₃₂N₄O₃, 473.25; found, 473.2. 5-2 biphenyl-2-ylcarbamic acid1-(2-{4-[(4-trifluoromethylbenzenesulfonylamino)methyl]phenylcarbamoyl}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₅H₃₅F₃N₄O₅S, 681.23; found, 681.1.

5-3 biphenyl-2-ylcarbamic acid 1-(2-{4-[(butane-1-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₂H₄₀N₄O₅S, 593.27; found, 593.2.

5-4 biphenyl-2-ylcarbamic acid 1-(2-{4-[(2-fluorobenzenesulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin- 4-yl ester. MSm/z: [M + H⁺] calcd for C₃₄H₃₅FN₄O₅S, 631.23; found, 631.2.

5-5 biphenyl-2-ylcarbamic acid 1-(2-{4-[(quinoline-8-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin- 4-yl ester. MSm/z: [M + H⁺] calcd for C₃₇H₃₇N₅O₅S, 664.25; found, 664.2.

5-6 biphenyl-2-ylcarbamic acid 1-{2-[4-(ethanesulfonylaminomethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺]calcd for C₃₀H₃₆N₄O₅S, 565.24; found, 565.2.

5-7 biphenyl-2-ylcarbamic acid 1-(2-{4-[(2,6-dichlorobenzenesulfonylamino)methyl]phenylcarbamoyl}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₄H₃₄Cl₂N₄O₅S, 681.16; found, 681.1.

5-8 biphenyl-2-ylcarbamic acid 1-(2-{4-[(toluene-4-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin- 4-yl ester. MSm/z: [M + H⁺] calcd for C₃₅H₃₈N₄O₅S, 627.26; found, 627.2.

5-9 biphenyl-2-ylcarbamic acid 1-(2-{4-[(thiophene-2-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin- 4-yl ester. MSm/z: [M + H⁺] calcd for C₃₂H₃₄N₄O₅S₂, 619.20; found, 619.1.

5-10 biphenyl-2-ylcarbamic acid 1-{2-[4-(benzenesulfonylaminomethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺]calcd for C₃₄H₃₆N₄O₅S, 613.24; found, 613.2.

5-11 biphenyl-2-ylcarbamic acid 1-{2-[4-(methanesulfonylaminomethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺]calcd for C₂₉H₃₄N₄O₅S, 551.23; found, 551.1.

5-12 biphenyl-2-ylcarbamic acid 1-{2-[4-(trifluoromethanesulfonylaminomethyl)phenylcarbamoyl]ethyl}piperidin- 4-yl ester. MS m/z:[M + H⁺] calcd for C₂₉H₃₁F₃N₄O₅S, 605.20; found, 605.1.

5-13 biphenyl-2-ylcarbamic acid 1-(2-{4-[(propane-1-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₁H₃₈N₄O₅S, 579.26; found, 579.2.

5-14 biphenyl-2-ylcarbamic acid 1-(2-{4-[(propane-2-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₁H₃₈N₄O₅S, 579.26; found, 579.2.

5-15 biphenyl-2-ylcarbamic acid 1-[2-(4-{[(pyridin-2-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin- 4-yl ester. MS m/z:[M + H⁺] calcd for C₃₄H₃₇N₅O₃, 564.29; found, 564.2.

5-16 biphenyl-2-ylcarbamic acid 1-[2-(4-{[(pyridin-3-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin- 4-yl ester. MS m/z:[M + H⁺] calcd for C₃₄H₃₇N₅O₃, 564.29; found, 564.2.

5-17 biphenyl-2-ylcarbamic acid 1-[2-(4-{[(pyridin-4-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin- 4-yl ester. MS m/z:[M + H⁺] calcd for C₃₄H₃₇N₅O₃, 564.29; found, 564.2.

5-18 biphenyl-2-ylcarbamic acid 1-[2-(4-{[(benzo[1,3]dioxol-5-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl] piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₆H₃₈N₄O₅, 607.28; found, 607.2.

5-19 biphenyl-2-ylcarbamic acid 1-[2-(4-{[(1H-indol-7-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin- 4-yl ester. MS m/z:[M + H ] calcd for C₃₇H₃₉N₅O₃, 602.31; found, 602.2.

5-20 biphenyl-2-ylcarbamic acid 1-{2-[4-(isobutylaminomethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺]calcd for C₃₂H₄₀N₄O₃, 529.31; found, 529.2.

5-21 biphenyl-2-ylcarbamic acid 1-[2-(4-{[(thiophen-2-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin- 4-yl ester. MS m/z:[M + H⁺] calcd for C₃₃H₃₆N₄O₃S, 569.25; found, 569.2.

5-22 biphenyl-2-ylcarbamic acid 1-(2-{4-[(3,3,3-trifluoropropylamino)methyl]phenylcarbamoyl}ethyl)piperidin- 4-yl ester. MS m/z:[M + H⁺] calcd for C₃₁H₃₅F₃N₄O₃, 569.27; found, 569.2.

5-23 biphenyl-2-ylcarbamic acid 1-(2-{4-[(2-methylaminoethanesulfonylamino)methyl]phenylcarbamoyl}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₁H₃₉N₅O₅S, 594.27; found, 594.2.

Example 6

Using the procedure of Example 1, substituting3-(4-formylphenyl)propionic acid in place of 4-carboxybenzaldehyde inPreparation 9 and using that product in place of the product ofPreparation 5, and substituting the appropriate amine in the reductiveamination step, the following compounds were prepared.

# Name —NR⁶R⁷ 6-1 biphenyl-2-ylcarbamic acid 1-{2-[3-(4-methylamino—NH(CH₃) methylphenyl)propionylamino]ethyl}piperidin-4-yl ester. MS m/z:[M + H⁺] calcd for C₃₁H₃₈N₄O₃, 515.29; found, 515.2. 6-2biphenyl-2-ylcarbamic acid 1-{2-[3-(4-ethylaminomethyl —NH(CH₂CH₃)phenyl)propionylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₂H₄₀N₄O₃, 529.31; found, 529.2. 6-3 biphenyl-2-ylcarbamic acid1-(2-{3-[4-(isopropylaminomethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₃H₄₂N₄O₃, 543.33; found, 543.2.

6-4 biphenyl-2-ylcarbamic acid 1-{2-[3-(4-cyclopropylaminomethylphenyl)propionylamino]ethyl} piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₃H₄₀N₄O₃, 541.31; found, 541.2.

6-5 biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(cyclopropylmethylamino)methyl]phenyl}propionylamino)ethyl] piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₄H₄₂N₄O₃, 555.33; found, 555.2.

6-6 biphenyl-2-ylcarbamic acid 1-{2-[3-(4-cyclopentylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺]calcd for C₃₅H₄₄N₄O₃, 569.34; found, 569.4.

6-7 biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(2-hydroxyethyl —NH[(CH₂)₂OH]amino)methyl]phenyl}propionylamino)ethyl]piperidin-4- yl ester. MS m/z:[M + H⁺] calcd for C₃₂H₄₀N₄O₄, 545.31; found, 545.2. 6-8biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[2-methoxyethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4- yl ester. MS m/z:[M + H⁺] calcd for C₃₃H₄₂N₄O₄, 559.32; found, 559.2.

6-9 biphenyl-2-ylcarbamic acid 1-(2-{3-[4-(4-acetyl-[1,4]diazepan-1-ylmethyl)phenyl]propionylamino}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₇H₄₇N₅O₄, 626.36; found, 626.4.

6-10 biphenyl-2-ylcarbamic acid 1-(2-{3-[4-(4-acetylpiperazin-1-ylmethyl)phenyl]propionylamino}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₆H₄₅N₅O₄, 612.35; found, 612.4.

6-11 biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(carbamoylmethylamino)methyl]phenyl}propionylamino)ethyl] piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₂H₃₉N₅O₄, 558.30; found, 558.2.

6-12 biphenyl-2-ylcarbamic acid 1-(2-{3-[4-(4-dimethylcarbamoylmethylpiperazin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₈H₅₀N₆O₄,655.39; found, 655.4.

6-13 4-[4-(2-{2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethylcarbamoyl}ethyl)benzyl]piperazine-1-carboxylic acid methylester. MS m/z: [M + H⁺] calcd for C₃₆H₄₅N₅O₅, 628.34; found, 628.2.

6-14 biphenyl-2-ylcarbamic acid 1-(2-{3-[4-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)phenyl]propionylamino}ethyl) piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₄H₄₂N₄O₅S, 619.29; found, 619.2.

6-15 biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{[bis-(2-hydroxy—N[(CH₂)₂OH]₂ ethyl)amino]methyl}phenyl)propionylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₄H₄₄N₄O₅, 589.33;found, 589.2. 6-16 biphenyl-2-ylcarbamic acid 1-(2-{3-[4-(4-dimethylcarbamoylpiperazin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₇H₄₈N₆O₄,641.37; found, 641.4.

6-17 biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[4-(pyrrolidine-1-carbonyl)piperazin-1-ylmethyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₉H₅₀N₆O₄,667.39; found, 667.4.

6-18 biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[4-(piperidine-1-carbonyl)piperazin-1-ylmethyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₄₀H₅₂N₆O₄,681.41; found, 681.4.

6-19 biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[4-(morpholine-4-carbonyl)piperazin-1-ylmethyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₉H₅₀N₆O₅,683.38; found, 683.4.

Preparation 16 4-(Formylphenyl)acetic Acid

4-(formylphenyl)acetic acid methyl ester was prepared as described inChem. Commun. 7:669-670 (2001). To a solution of (4-formylphenyl)aceticacid methyl ester (2.76 g, 14.4 mmol) in 40 mL of MeOH was added 1N NaOH(30 ml). The solution was stirred at room temperature for 16 hours andthen the MeOH was removed in vacuo. The aqueous layer was then washedwith EtOAc (40 mL), followed by wash with DCM (40 mL). The aqueous layerwas then acidified to pH=1 using 1N HCl. The product was extracted usingDCM washes (3×50 mL) and the organic layer washed with water (100 mL),NaCl (sat.) (100 mL), dried over MgSO₄ and then filtered. The solventremoved under reduced pressure. The crude material was sufficiently pureto use without further purification. The title compound was obtained in78% yield (2.0 g, 11.2 mmol).

Example 7

Using the procedure of Example 1, substituting 4-(formylphenyl)aceticacid (prepared as described in Preparation 16) in place of4-carboxybenzaldehyde in Preparation 9 and using that product in placeof the product of Preparation 5, and substituting the appropriate aminein the reductive amination step, the following compounds were prepared.

# Name —NR⁶R⁷ 7-1 biphenyl-2-ylcarbamic acid 1-{2-[2-(4-methylamino—NH(CH₃) methylphenyl)acetylamino]ethyl}piperidin-4-yl ester. MS m/z:[M + H⁺] calcd for C₃₀H₃₆N₄O₃, 501.28 found, 501.2. 7-2biphenyl-2-ylcarbamic acid 1-{2-[2-(4-ethylaminomethyl —NH(CH₂CH₃)phenyl)acetylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcdfor C₃₁H₃₈N₄O₃, 515.29; found, 515.2. 7-3 biphenyl-2-ylcarbamic acid1-[2-(2-{4-[(2-hydroxyethyl —NH[(CH₂)₂OH]amino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₁H₃₈N₄O₄, 531.29; found, 531.2. 7-4biphenyl-2-ylcarbamic acid 1-[2-(2-{4-[(2-methoxyethylamino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₂H₄₀N₄O₄, 545.31; found, 545.2.

7-5 biphenyl-2-ylcarbamic acid 1-[2-(2-{4-[(carbamoylmethylamino)methyl]phenyl}acetylamino)ethyl] piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₁H₃₇N₅O₄, 544.28; found, 544.2.

7-6 biphenyl-2-ylcarbamic acid 1-(2-{2-[4-(4-dimethylcarbamoylpiperazin-1-ylmethyl)phenyl]acetylaminol} ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₆H₄₆N₆O₄, 627.36; found, 627.4.

Preparation 17 4-Formyl-3-methoxybenzoic Acid Methyl Ester

To a stirred solution of 4-bromo-3-methoxybenzoic acid (15.0 g, 58 mmol)in DMSO (150 mL) was added NaHCO₃ (20.0 g, 230 mmol). This was heated to80° C. for 18 hours. The reaction was then cooled to room temperatureand the solvent removed under reduced pressure. The crude reactionmixture was then dissolved in DCM (200 mL) and washed with 1N HCl (100mL), water (100 mL), NaCl (sat.) (100 mL), dried over MgSO₄ and thenfiltered. The solvent was removed under reduced pressure. The crudematerial was sufficiently pure to use without further purification. Thetitle intermediate was obtained in 79% yield (8.9 g, 45.8 mmol).

Preparation 18 2-Methoxyterephthalic Acid 4-Methyl Ester

To a stirred solution of 4-formyl-3-methoxybenzoic acid methyl ester(5.0 g, 26 mmol; prepared as described in Preparation 17) in tert-butylalcohol (200 mL) was added NaH₂PO₄-2H₂O (3.6 g, 26 mmol), water (50 mL),2-methyl-2-butene (11 mL, 104 mmol), and finally NaClO₂ (7.02 g, 78mmol). The reaction was allowed to stir at room temperature for 4 hours.The solvent was then removed under reduced pressure. The crude reactionmixture was then dissolved in DCM (200 mL) and the product was extractedwith 1N NaOH (200 mL). The aqueous layer was washed with DCM (200 mL)and then neutralized with 6N HCl (˜40 mL) and the product extracted withDCM (200 mL). The organic layer was then washed with water (100 mL),NaCl (sat.) (100 mL), dried over MgSO₄ and then filtered. The solventwas removed under reduced pressure. The crude material was sufficientlypure to use without further purification. The title intermediate wasobtained in 47% yield (2.4 g, 12.3 mmol).

Preparation 19N-{2-[4-(Biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}-3-methoxy-N-methylterephthalamicAcid Methyl Ester

To a stirred solution of 2-methoxyterephthalic acid 4-methyl ester (450mg, 2.1 mmol; prepared as described in Preparation 18) in DMF (10 mL)was added EDC (630 mg, 3.3 mmol), HOAt (2.4 mL, 1.18 mmol, 0.5M in DMF)and DIPEA (1.3 mL, 7.05 mmol). When the mixture was homogenous, asolution of biphenyl-2-ylcarbamic acid1-(2-methylaminoethyl)piperidin-4-yl ester (830 mg, 2.4 mmol; preparedas described in Preparation 4) was added slowly. The reaction mixturewas stirred at room temperature for 16 hours and then washed with water(100 mL), 1N HCl (100 mL), 1N NaOH (100 mL), brine (100 mL), dried overMgSO₄, filtered and concentrated to afford the title intermediate in 89%yield (1.04 g, 1.9 mmol). MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₃O₆, 545.6;found, 546.6.

Preparation 20 Biphenyl-2-ylcarbamic Acid1-{2-[(4-hydroxymethyl-2-methoxybenzoyl)methylamino]ethyl}piperidin-4-ylEster

To a stirred solution ofN-{2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}-3-methoxy-n-methylterephthalamicacid methyl ester (1.0 g, 1.8 mmol; prepared as described in Preparation19) in THF (100 mL) at 0° C., was added MeOH (57 μL, 1.8 mmol), followedby LiAlH₄ (1.8 mL, 1.8 mmol, 1.0M in THF) was added. The ice bath wasremoved, and the reaction mixture was stirred at room temperature for 1hour. The reaction was quenched with 1N HCl (aq) at 0° C. until no morebubbling, and stirring was continued for 10 minutes. The solvent wasremoved under reduced pressure. The crude reaction mixture was taken upin DCM (100 mL) and washed with water (100 mL), NaCl (sat.) (100 mL),dried over MgSO₄ and then filtered. The solvent was removed underreduced pressure. The crude material was sufficiently pure to usewithout further purification. The title intermediate was obtained in 89%yield (831 mg, 1.6 mmol). MS m/z: [M+H⁺] calcd for C₃₀H₃₅N₃O₅, 517.6;found, 518.6.

Preparation 21 Biphenyl-2-ylcarbamic acid1-{2-[(4-formyl-2-methoxybenzoyl)methylamino]ethyl}piperidin-4-yl Ester

To a stirred solution of biphenyl-2-ylcarbamic acid1-{2-[(4-hydroxymethyl-2-methoxybenzoyl)methylamino]ethyl}piperidin-4-ylester (78 mg, 1.5 mmol; prepared as described in Preparation 20) in DCM(2.5 mL) at −15° C. was added DMSO (130 μL, 22.5 mmol), and DIPEA (130μL, 7.5 mmol). To the solution was added sulfur trioxide-pyridinecomplex (240 mg, 15 mmol). After 30 minutes, the reaction mixture wasquenched with water (˜3 mL). Two layers were separated, the organiclayer was dried over MgSO₄, filtered and the title intermediate was useddirectly in the next reaction.

Example 8

Using the procedure of Example 1, but substituting biphenyl-2-ylcarbamicacid 1-{2-[(4-formyl-2-methoxybenzoyl)methylamino]ethyl}piperidin-4-ylester (prepared as described in Preparation 21) in place of the productof Preparation 5, and substituting the appropriate amine in thereductive amination step, the following compounds were prepared.

# Name —NR⁶R⁷ 8-1 biphenyl-2-ylcarbamic acid 1-{2-[(2-methoxy- —NH(CH₃)4-methyl aminomethylbenzoyl)methylamino]- ethyl}piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₁H₃₈N₄O₄, 531.29; found, 531.2. 8-2biphenyl-2-ylcarbamic acid 1-(2-{[2-methoxy-4-(3-oxopiperazin-1-ylmethyl)benzoyl]- methylamino}ethyl) piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₄H₄₁N₅O₅, 600.31; found, 600.2.

8-3 biphenyl-2-ylcarbamic acid 1-[2-({4-[(2- —NH[(CH₂)₂OH] hydroxyethylamino)methyl]-2- methoxybenzoyl}methylamino)ethyl] piperidin- 4-ylester. MS m/z: [M + H⁺] calcd for C₃₂H₄₀N₄O₅, 561.30; found, 561.2.

Example 9

Using the procedure of Example 8, but substituting biphenyl-2-ylcarbamicacid 1-(2-aminoethyl)piperidin-4-yl ester (prepared as described inPreparation 7) in place of the product of Preparation 4 in Preparation19 and substituting the appropriate amine in the reductive aminationstep, the following compounds were prepared.

# Name —NR⁶R⁷ 9-1 biphenyl-2-ylcarbamic acid 1-[2-(2-methoxy- —NH(CH₃)4-methyl aminomethylbenzoylamino)ethyl]- piperidin-4-yl ester. MS m/z:[M + H⁺] calcd for C₃₀H₃₆N₄O₄, 517.27; found, 517.2. 9-2biphenyl-2-ylcarbamic acid 1-{2-[2-methoxy-4-(3-oxopiperazin-1-ylmethyl)benzoylamino]- ethyl}piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₃H₃₉N₅O₅, 586.30; found, 586.2.

9-3 biphenyl-2-ylcarbamic acid 1-(2-{4-[(2- —NH[(CH₂)₂OH] hydroxyethylamino)methyl]-2-methoxy- benzoylamino}ethyl)piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₁H₃₈N₄O₅, 547.28; found, 547.2.

Example 10

Using the procedure of Example 1, but substituting5-formylpyridine-2-carboxylic acid in place of 4-carboxybenzaldehyde inPreparation 5, and substituting the appropriate amine in the reductiveamination step, the following compounds were prepared.

# Name —NR⁶R⁷ 10-1 biphenyl-2-ylcarbamic acid 1-{2-[methyl(5-methylamino—NH(CH₃) methylpyridine-2-carbonyl)amino]ethyl}piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₂₉H₃₅N₅O₃, 502.27; found, 502.2. 10-2biphenyl-2-ylcarbamic acid 1-{2-[(5-diethylaminomethyl —N(CH₂CH₃)₂pyridine-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₂H₄₁N₅O₃, 544.32; found, 544.2. 10-3biphenyl-2-ylcarbamic acid 1-[2-({5-[(2-hydroxyethyl —NH[(CH₂)₂OH]amino)methyl]pyridine-2-carbonyl}methylamino)ethyl] piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₀H₃₇N₅O₄, 532.28; found, 532.2. 10-4biphenyl-2-ylcarbamic acid 1-{2-[methyl(5-morpholin-4-ylmethylpyridine-2-carbonyl)amino]ethyl}piperidin-4-yl ester. MS m/z:[M + H⁺] calcd for C₃₂H₃₉N₅O₄, 558.30; found, 558.2.

10-5 biphenyl-2-ylcarbamic acid 1-{2-[(5-{[(furan-2-ylmethyl)amino]methyl}pyridine-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₃H₃₇N₅O₄,568.28; found, 568.2.

10-6 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-formylpiperazin-1-ylmethyl)pyridine-2-carbonyl]methylamino}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₃H₄₀N₆O₄, 585.31; found, 585.2.

10-7 biphenyl-2-ylcarbamic acid 1-{2-[(5-{[bis-(2-hydroxy —N[(CH₂)₂OH]₂ethyl)amino]methyl}pyridine-2-carbonyl)methylamino] ethyl}piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₂H₄₁N₅O₅, 576.31; found, 576.2. 10-8biphenyl-2-ylcarbamic acid 1-(2-{methyl-[5-(3-oxo-piperazin-1-ylmethyl)pyridine-2-carbonyl]amino}ethyl) piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₂H₃₈N₆O₄, 571.30; found, 571.2.

10-9 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-acetyl-[1,4]diazepan-1-ylmethyl)pyridine-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₅H₄₄N₆O₄,613.34; found, 613.4.

10-10 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-acetylpiperazin-1-ylmethyl)pyridine-2-carbonyl]methylamino}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₄H₄₂N₆O₄, 599.33; found, 599.2.

10-11 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-methanesulfonylpiperazin-1-ylmethyl)pyridine-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₃H₄₂N₆O₅S,635.29; found, 635.2.

10-12 4-[6-({2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}methylcarbamoyl)pyridin-3-ylmethyl]piperazine- 1-carboxylic acidmethyl ester. MS m/z: [M + H⁺] calcd for C₃₄H₄₂N₆O₅, 615.32; found,615.2.

Example 11

Using the procedure of Example 1, but substituting5-formylthiophene-2-carboxylic acid in place of 4-carboxybenzaldehyde inPreparation 5, and substituting the appropriate amine in the reductiveamination step, the following compounds were prepared.

# Name —NR⁶R⁷ 11-1 biphenyl-2-ylcarbamic acid 1-{2-[methyl-(5-methyl—NH(CH₃) aminomethylthiophene-2-carbonyl)amino]ethyl} piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₂₈H₃₄N₄O₃S, 507.24; found, 507.2.11-2 biphenyl-2-ylcarbamic acid 1-{2-[(5-diethylaminomethyl —N(CH₂CH₃)₂thiophene-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z:[M + H⁺] calcd for C₃₁H₄₀N₄O₃S, 549.28; found, 549.2. 11-3biphenyl-2-ylcarbamic acid 1-[2-({5-[(2-hydroxyethyl —NH[(CH₂)₂OH]amino)methyl]thiophene-2-carbonyl}methylamino)ethyl] piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₂₉H₃₆N₄O₄S, 537.25; found, 537.2.11-4 biphenyl-2-ylcarbamic acid 1-{2-[methyl-(5-morpholin-4-ylmethylthiophene-2-carbonyl)amino]ethyl}piperidin- 4-yl ester. MSm/z: [M + L{⁺] calcd for C₃₁H₃₈N₄O₄S, 563.26; found, 563.2.

11-5 biphenyl-2-ylcarbamic acid 1-{2-[(5-{[(furan-2-ylmethyl)amino]methyl}thiophene-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₂H₃₆N₄O₄S, 573.25; found, 573.2.

11-6 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-formylpiperazin-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₂H₃₉N₅O₄S, 590.27; found, 590.2.

11-7 biphenyl-2-ylcarbamic acid 1-{2-[(5-{[bis-(2-hydroxy- —N[(CH₂)₂OH]₂ethyl)amino]methyl}thiophene-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₃₁H₄₀N₄O₅S,581.27; found, 581.2. 11-8 biphenyl-2-yl-carbamic acid1-(2-{methyl-[5-(3-oxopiperazin-1-ylmethyl)thiophene-2-carbonyl]amino}ethyl) piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₁H₃₇N₅O₄S, 576.26; found, 576.2.

11-9 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-acetyl-[1,4]diazepan-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₄H₄₃N₅O₄S, 618.30; found, 618.2.

 11-10 4-[5-({2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}methylcarbamoyl)thiophen-2-ylmethyl]piperazine- 1-carboxylic acidmethyl ester. MS m/z: [M + H⁺] calcd for C₃₃H₄₁N₅O₅S, 620.28; found,620.2.

 11-11 biphenyl-2-ylcarbamic acid 1-(2-{[5-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₁H₃₈N₄O₅S₂, 611.23; found, 611.2.

 11-12 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-acetylpiperazin-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₃H₄₁N₅O₄S, 604.29; found, 604.2.

 11-13 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-methanesulfonylpiperazin-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₂H₄₁N₅O₅S₂, 640.26; found, 640.2.

Example 12

Using the procedure of Example 1, substituting5-formylthiophene-2-carboxylic acid in place of 4-carboxybenzaldehyde inPreparation 9 and using that product in place of the product ofPreparation 5, and substituting the appropriate amine in the reductiveamination step, the following compounds were prepared.

# Name —NR⁶R⁷ 12-1 biphenyl-2-ylcarbamic acid 1-{2-[(5- —NH(CH₃)methylaminomethyl thiophene-2-carbonyl) amino]ethyl}piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₂₇H₃₂N₄O₃S, 493.22; found, 493.2.12-2 biphenyl-2-ylcarbamic acid 1-[2-({5-[(2- —NH[(CH₂)₂OH] hydroxyethylamino)methyl]thiophene-2- carbonyl}amino)ethyl]piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₂₈H₃₄N₄O₄S, 523.23; found, 523.2.

Example 13

Using the procedure of Example 1, substituting4-formylpyrrole-2-carboxylic acid in place of 4-carboxybenzaldehyde inPreparation 9 and using that product in place of the product ofPreparation 5, and substituting the appropriate amine in the reductiveamination step, Compound 13-1 (R⁶=H, R⁷=—CH₃) was prepared:biphenyl-2-ylcarbamic acid 1-{2-[methyl(4-methylaminomethyl-1H-pyrrole-2-carbonyl)amino]ethyl}piperidin-4-yl ester. MS m/z:[M+H⁺] calcd for C₂₈H₃₅N₅O₃, 490.27; found, 490.2.

Example 14

Using the procedure of Example 1, but substituting5-formylpyrrole-2-carboxylic acid in place of 4-carboxybenzaldehyde inPreparation 5, and substituting the appropriate amine in the reductiveamination step, the following compounds were prepared.

# Name —NR⁶R⁷ 14-1 biphenyl-2-ylcarbamic acid 1-{2-[methyl-(5-methyl—NH(CH₃) aminomethyl-1H-pyrrole-2-carbonyl)amino]ethyl} piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₂₈H₃₅N₅O₃, 490.27; found, 490.2. 14-2biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-acetylpiperazin-1-ylmethyl)-1H-pyrrole-2-carbonyl]methylamino}ethyl) piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₃H₄₂N₆O₄, 587.33; found, 587.2.

14-3 biphenyl-2-ylcarbamic acid 1-[2-({5-[(2-hydroxyethyl —NH[(CH₂)₂OH]amino)methyl]-1H-pyrrole-2-carbonyl}methylamino) ethyl]piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₂₉H₃₇N₅O₄, 520.28; found, 520.2.

Example 15

Using the procedure of Example 1, but substituting5-formylfuran-2-carboxylic acid in place of 4-carboxybenzaldehyde inPreparation 5, and substituting the appropriate amine in the reductiveamination step, the following compounds were prepared.

# Name —NR⁶R⁷ 15-1 biphenyl-2-ylcarbamic acid 1-{2-[methyl(5-methylamino—NH(CH₃) methylfuran-2-carbonyl)amino]ethyl}piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₂₈H₃₄N₄O₄, 491.26; found, 491.6. 15-2biphenyl-2-ylcarbamic acid 1-{2-[(5-diethylaminomethyl —N(CH₂CH₃)₂furan-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₁H₄₀N₄O₄, 533.31; found, 533.2. 15-3biphenyl-2-ylcarbamic acid 1-[2-({5-[(2-hydroxyethyl —NH[(CH₂)₂OH]amino)methyl]furan-2-carbonyl}methylamino)ethyl] piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₂₉H₃₆N₄O₅, 521.27; found, 521.2. 15-4biphenyl-2-ylcarbamic acid 1-{2-[methyl(5-morpholin-4-ylmethylfuran-2-carbonyl)amino]ethyl}piperidin-4-yl ester. MS m/z: [M +H⁺] calcd for C₃₁H₃₈N₄O₅, 547.28; found, 547.2.

15-5 biphenyl-2-ylcarbamic acid 1-{2-[(5-{[(furan-2-ylmethyl)amino]methyl}furan-2-carbonyl)methylamino] ethyl}piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₂H₃₆N₄O₅, 557.27; found, 557.2.

15-6 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-formylpiperazin-1-ylmethyl)furan-2-carbonyl]methylamino}ethyl) piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₂H₃₉N₅O₅, 574.30; found, 574.2.

15-7 biphenyl-2-ylcarbamic acid 1-{2-[(5-{[bis-(2-hydroxy —N[(CH₂)₂OH]₂ethyl)amino]methyl}furan-2-carbonyl)methylamino] ethyl}piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₁H₄₀N₄O₆, 565.29; found, 565.2. 15-8biphenyl-2-yl-carbamic acid 1-(2-{methyl-[5-(3-oxopiperazin-1-ylmethyl)furan-2-carbonyl]amino}ethyl) piperidin-4-yl ester.MS m/z: [M + H⁺] calcd for C₃₁H₃₇N₅O₅, 560.28; found, 560.2.

15-9 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-acetyl[1,4]diazepan-1-ylmethyl)furan-2-carbonyl]ethylamino}ethyl) piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₄H₄₃N₅O₅, 602.33; found, 602.4.

15-10 4-[5-({2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}methylcarbamoyl)furan-2-ylmethyl]piperazine- 1-carboxylic acidmethyl ester. MS m/z: [M + H⁺] calcd for C₃₃H₄₁N₅O₆, 604.31; found,604.2.

15-11 biphenyl-2-ylcarbamic acid 1-(2-{[5-(1,1-dioxo-1λ⁶-thiomorpholin-4-ylmethyl)furan-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester. MS m/z: [M + H⁺] calcd forC₃₁H₃₈N₄O₆S, 595.25; found, 595.2.

15-12 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-acetylpiperazin-1-ylmethyl)furan-2-carbonyl]methylamino}ethyl) piperidin-4-yl ester. MSm/z: [M + H⁺] calcd for C₃₃H₄₁N₅O₅, 588.31; found, 588.2.

15-13 biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-methanesulfonylpiperazin-1-ylmethyl)furan-2-carbonyl]methylamino} ethyl)piperidin-4-ylester. MS m/z: [M + H⁺] calcd for C₃₂H₄₁N₅O₆S, 624.28; found, 624.2.

Example 16

Using the procedure of Example 1, substituting5-formylfuran-2-carboxylic acid in place of 4-carboxybenzaldehyde inPreparation 9 and using that product in place of the product ofPreparation 5, and substituting the appropriate amine in the reductiveamination step, the following compounds were prepared.

# Name —NR⁶R⁷ 16-1 biphenyl-2-yl-carbamic acid 1-{2-[(5- —NH₂aminomethylfuran-2-carbonyl)amino]ethyl} piperidin-4-yl ester. MS m/z:[M + H⁺] calcd for C₂₆H₃₀N₄O₄, 463.23. 16-2 biphenyl-2-yl-carbamic acid1-{2-[(5- —NH(CH₃) methylamino methylfuran-2-carbonyl)amino]ethyl}piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₂₇H₃₂N₄O₄,477.24; found, 477.2. 16-3 biphenyl-2-ylcarbamic acid 1-[2-({5-[(2-—NH[(CH₂)₂OH] hydroxyethyl amino)methyl]furan-2-carbonyl}amino)ethyl]piperidin-4-yl ester. MS m/z: [M + H⁺] calcd for C₂₈H₃₄N₄O₅,507.25; found, 507.2.

Assay 1 Radioligand Binding Assay Membrane Preparation from CellsExpressing hM₁, hM₂, hM₃ and hM₄ Muscarinic Receptor Subtypes

CHO cell lines stably expressing cloned human hM₁, hM₂, hM₃ and hM₄muscarinic receptor subtypes, respectively, were grown to nearconfluency in medium consisting of HAM's F-12 supplemented with 10% FBSand 250 μg/mL Geneticin. The cells were grown in a 5% CO₂, 37° C.incubator and lifted with 2 mM EDTA in dPBS. Cells were collected by 5minute centrifugation at 650×g, and cell pellets were either storedfrozen at −80° C. or membranes were prepared immediately. For membranepreparation, cell pellets were resuspended in lysis buffer andhomogenized with a Polytron PT-2100 tissue disrupter (Kinematica AG; 20seconds×2 bursts). Crude membranes were centrifuged at 40,000×g for 15minutes at 4° C. The membrane pellet was then resuspended withresuspension buffer and homogenized again with the Polytron tissuedisrupter. The protein concentration of the membrane suspension wasdetermined by the method described in Lowry, O. et al., Journal ofBiochemistry 193:265 (1951). All membranes were stored frozen inaliquots at −80° C. or used immediately. Aliquots of prepared hM₅receptor membranes were purchased directly from Perkin Elmer and storedat −80° C. until use.

Radioligand Binding Assay on Muscarinic Receptor Subtypes hM₁, hM₂, hM₃,hM₄ and hM₅

Radioligand binding assays were performed in 96-well microtiter platesin a total assay volume of 100 μL. CHO cell membranes stably expressingeither the hM₁, hM₂, hM₃, hM₄ or hM₅ muscarinic subtype were diluted inassay buffer to the following specific target protein concentrations(μg/well): 10 μg for hM₁, 10-15 μg for hM₂, 10-20 μg for hM₃, 10-20 μgfor hM₄, and 10-12 μg for hM₅. The membranes were briefly homogenizedusing a Polytron tissue disruptor (10 seconds) prior to assay plateaddition. Saturation binding studies for determining K_(D) values of theradioligand were performed using L-[N-methyl-³H]scopolamine methylchloride ([³H]-NMS) (TRK666, 84.0 Ci/mmol, Amersham Pharmacia Biotech,Buckinghamshire, England) at concentrations ranging from 0.001 nM to 20nM. Displacement assays for determination of K_(i) values of testcompounds were performed with [³H]-NMS at 1 nM and eleven different testcompound concentrations. The test compounds were initially dissolved toa concentration of 400 μM in dilution buffer and then serially diluted5× with dilution buffer to final concentrations ranging from 10 pM to100 μM. The addition order and volumes to the assay plates were asfollows: 25 μL radioligand, 25 μL diluted test compound, and 50 μLmembranes. Assay plates were incubated for 60 minutes at 37° C. Bindingreactions were terminated by rapid filtration over GF/B glass fiberfilter plates (PerkinElmer Inc., Wellesley, Mass.) pre-treated in 1%BSA. Filter plates were rinsed three times with wash buffer (10 mMHEPES) to remove unbound radioactivity. Plates were then air dried, and50 μL Microscint-20 liquid scintillation fluid (PerkinElmer Inc.,Wellesley, Mass.) was added to each well. The plates were then countedin a PerkinElmer Topcount liquid scintillation counter (PerkinElmerInc., Wellesley, Mass.). Binding data were analyzed by nonlinearregression analysis with the GraphPad Prism Software package (GraphPadSoftware, Inc., San Diego, Calif.) using the one-site competition model.K_(i) values for test compounds were calculated from observed IC₅₀values and the K_(D) value of the radioligand using the Cheng-Prusoffequation (Cheng Y; Prusoff W. H. Biochemical Pharmacology22(23):3099-108 (1973)). K_(i) values were converted to pK_(i) values todetermine the geometric mean and 95% confidence intervals. These summarystatistics were then converted back to K_(i) values for data reporting.In this assay, a lower K_(i) value indicates that the test compound hasa higher binding affinity for the receptor tested. Exemplary compoundsof the invention that were tested in this or a similar assay, typicallywere found to have a K_(i) value of less than about 10 nM for the M₃muscarinic receptor subtype.

Assay 2 Muscarinic Receptor Functional Potency Assays Blockade ofAgonist-Mediated Inhibition of cAMP Accumulation

In this assay, the functional potency of a test compound is determinedby measuring the ability of the test compound to blockoxotremorine-inhibition of forskolin-mediated cAMP accumulation inCHO-K1 cells expressing the hM₂ receptor. cAMP assays are performed in aradioimmunoassay format using the Flashplate Adenylyl Cyclase ActivationAssay System with ¹²⁵I-cAMP (NEN SMP004B, PerkinElmer Life SciencesInc., Boston, Mass.), according to the manufacturer's instructions.

Cells are rinsed once with dPBS and lifted with Trypsin-EDTA solution(0.05% trypsin/0.53 mM EDTA) as described in the Cell Culture andMembrane Preparation section above. The detached cells are washed twiceby centrifugation at 650×g for five minutes in 50 mLs dPBS. The cellpellet is then re-suspended in 10 mL dPBS, and the cells are countedwith a Coulter Z1 Dual Particle Counter (Beckman Coulter, Fullerton,Calif.). The cells are centrifuged again at 650×g for five minutes andre-suspended in stimulation buffer to an assay concentration of1.6×10⁶-2.8×10⁶ cells/mL.

The test compound is initially dissolved to a concentration of 400 μM indilution buffer (dPBS supplemented with 1 mg/mL BSA (0.1%)), and thenserially diluted with dilution buffer to final molar concentrationsranging from 100 μM to 0.1 nM. Oxotremorine is diluted in a similarmanner. To measure oxotremorine inhibition of adenylyl cyclase (AC)activity, 25 μL forskolin (25 μM final concentration diluted in dPBS),25 μL diluted oxotremorine, and 50 μL cells are added to agonist assaywells. To measure the ability of a test compound to blockoxotremorine-inhibited AC activity, 25 μL forskolin and oxotremorine (25μM and 5 μM final concentrations, respectively, diluted in dPBS) 25 μLdiluted test compound, and 50 μL cells are added to remaining assaywells.

Reactions are incubated for 10 minutes at 37° C. and stopped by additionof 100 μL ice-cold detection buffer. Plates are sealed, incubatedovernight at room temperature and counted the next morning on aPerkinElmer TopCount liquid scintillation counter (PerkinElmer Inc.,Wellesley, Mass.). The amount of cAMP produced (pmol/well) is calculatedbased on the counts observed for the samples and cAMP standards, asdescribed in the manufacturer's user manual. Data are analyzed bynonlinear regression analysis with the GraphPad Prism Software package(GraphPad Software, Inc., San Diego, Calif.) using the non-linearregression, one-site competition equation. The Cheng-Prusoff equation isused to calculate the K_(i), using the EC₅₀ of the oxotremorineconcentration-response curve and the oxotremorine assay concentration asthe K_(D) and [L], respectively. The K_(i) values are converted topK_(i) values to determine the geometric mean and 95% confidenceintervals. These summary statistics are then converted back to K_(i)values for data reporting. In this assay, a lower K_(i) value indicatesthat the test compound has a higher functional activity at the receptortested. Compounds of the invention are expected to have a K_(i) value ofless than about 10 nM for blockade of oxotremorine-inhibition offorskolin-mediated cAMP accumulation in CHO-K1 cells expressing the hM₂receptor, when tested in this or a similar assay.

Blockade of Agonist-Mediated [³⁵S]GTPγS Binding

In a second functional assay, the functional potency of test compoundscan be determined by measuring the ability of the compounds to blockoxotremorine-stimulated [³⁵S]GTPγS binding in CHO-K1 cells expressingthe hM₂ receptor. At the time of use, frozen membranes are thawed andthen diluted in assay buffer with a final target tissue concentration of5-10 μg protein per well. The membranes are briefly homogenized using aPolytron PT-2100 tissue disrupter and then added to the assay plates.

The EC₉₀ value (effective concentration for 90% maximal response) forstimulation of [³⁵S]GTPγS binding by the agonist oxotremorine isdetermined in each experiment. To determine the ability of a testcompound to inhibit oxotremorine-stimulated [³⁵S]GTPγS binding, thefollowing is added to each well of 96 well plates: 25 μL of assay bufferwith [³⁵S]GTPγS (0.4 nM), 25 μL of oxotremorine (EC₉₀) and GDP (3 μM),25 μL of diluted test compound and 25 μL CHO cell membranes expressingthe hM₂ receptor. The assay plates are then incubated at 37° C. for 60minutes. The assay plates are filtered over 1% BSA-pretreated GF/Bfilters using a PerkinElmer 96-well harvester. The plates are rinsedwith ice-cold wash buffer for 3×3 seconds and then air or vacuum dried.Microscint-20 scintillation liquid (50 μL) is added to each well, andeach plate is sealed and radioactivity counted on a topcounter(PerkinElmer). Data are analyzed by nonlinear regression analysis withthe GraphPad Prism Software package (GraphPad Software, Inc., San Diego,Calif.) using the non-linear regression, one-site competition equation.The Cheng-Prusoff equation is used to calculate the K_(i), using theIC₅₀ values of the concentration-response curve for the test compoundand the oxotremorine concentration in the assay as the K_(D) and [L],ligand concentration, respectively. In this assay, a lower K_(i) valueindicates that the test compound has a higher functional activity at thereceptor tested. Compounds of the invention are expected to have a K_(i)value of less than about 10 nM for blockade of oxotremorine-stimulated[³⁵S]GTPγS-binding in CHO-K1 cells expressing the hM₂ receptor, whentested in this or a similar assay.

Blockade of Agonist-Mediated Calcium Release Via FLIPR Assays

Muscarinic receptor subtypes (M₁, M₃ and M₅ receptors), which couple toG_(q) proteins, activate the phospholipase C (PLC) pathway upon agonistbinding to the receptor. As a result, activated PLC hydrolyzesphosphatyl inositol diphosphate (PIP₂) to diacylglycerol (DAG) andphosphatidyl-1,4,5-triphosphate (IP₃), which in turn generates calciumrelease from intracellular stores, i.e., endoplasmic and sarcoplasmicreticulum. The FLIPR (Molecular Devices, Sunnyvale, Calif.) assaycapitalizes on this increase in intracellular calcium by using a calciumsensitive dye (Fluo-4AM, Molecular Probes, Eugene, Oreg.) thatfluoresces when free calcium binds. This fluorescence event is measuredin real time by the FLIPR, which detects the change in fluorescence froma monolayer of cells cloned with human M₁ and M₃, and chimpanzee M₅receptors. Antagonist potency can be determined by the ability ofantagonists to inhibit agonist-mediated increases in intracellularcalcium. For FLIPR calcium stimulation assays, CHO cells stablyexpressing the hM₁, hM₃ and cM₅ receptors are seeded into 96-well FLIPRplates the night before the assay is done. Seeded cells are washed twiceby Cellwash (MTX Labsystems, Inc.) with FLIPR buffer (10 mM HEPES, pH7.4, 2 mM calcium chloride, 2.5 mM probenecid in Hank's Buffered SaltSolution (HBSS) without calcium and magnesium) to remove growth mediaand leaving 50 μL/well of FLIPR buffer. The cells are then incubatedwith 50 μL/well of 4 μM FLUO-4AM (a 2× solution was made) for 40 minutesat 37° C., 5% carbon dioxide. Following the dye incubation period, cellsare washed two times with FLIPR buffer, leaving a final volume of 50μL/well.

To determine antagonist potency, the dose-dependent stimulation ofintracellular Ca²⁺ release for oxotremorine is first determined so thatantagonist potency can later be measured against oxotremorinestimulation at an EC₉₀ concentration. Cells are first incubated withcompound dilution buffer for 20 minutes, followed by agonist addition,which is performed by the FLIPR. An EC₉₀ value for oxotremorine isgenerated according to the method detailed in the FLIPR measurement anddata reduction section below, in conjunction with the formulaEC_(F)=((F/100−F)^1/H)*EC₅₀. An oxotremorine concentration of 3×EC_(F)is prepared in stimulation plates such that an EC₉₀ concentration ofoxotremorine is added to each well in the antagonist inhibition assayplates. The parameters used for the FLIPR are: exposure length of 0.4seconds, laser strength of 0.5 watts, excitation wavelength of 488 nm,and emission wavelength of 550 nm. Baseline is determined by measuringthe change in fluorescence for 10 seconds prior to addition of agonist.Following agonist stimulation, the FLIPR continuously measured thechange of fluorescence every 0.5 to 1 second for 1.5 minutes to capturethe maximum fluorescence change. The change of fluorescence is expressedas maximum fluorescence minus baseline fluorescence for each well. Theraw data is analyzed against the logarithm of drug concentration bynonlinear regression with GraphPad Prism (GraphPad Software, Inc., SanDiego, Calif.) using the built-in model for sigmoidal dose-response.Antagonist K_(i) values are determined by Prism using the oxotremorineEC₅₀ value as the K_(D) and the oxotremorine EC₉₀ for the ligandconcentration according to the Cheng-Prusoff equation (Cheng & Prusoff,1973). In this assay, a lower K_(i) value indicates that the testcompound has a higher functional activity at the receptor tested.Compounds of the invention are expected to have a K_(i) value of lessthan about 10 nM for blockade of agonist-mediated calcium release in CHOcells stably expressing the hM₃ receptor, when tested in this or asimilar assay.

Assay 3 Determination of Duration of Bronchoprotection in Guinea PigModel of Acetylcholine-Induced Bronchoconstriction

This in vivo assay is used to assess the bronchoprotective effects oftest compounds exhibiting muscarinic receptor antagonist activity.Groups of six male guinea pigs (Duncan-Hartley (HsdPoc:DH) Harlan,Madison, Wis.) weighing between 250 and 350 g are individuallyidentified by cage cards. Throughout the study animals are allowedaccess to food and water ad libitum. Test compounds are administered viainhalation over 10 minutes in a whole-body exposure dosing chamber (R&SMolds, San Carlos, Calif.). The dosing chambers are arranged so that anaerosol was simultaneously delivered to 6 individual chambers from acentral manifold. Guinea pigs are exposed to an aerosol of a testcompound or vehicle (WFI). These aerosols are generated from aqueoussolutions using an LC Star Nebulizer Set (Model 22F51, PARI RespiratoryEquipment, Inc. Midlothian, Va.) driven by a mixture of gases (CO₂=5%,O₂=21% and N₂=74%) at a pressure of 22 psi. The gas flow through thenebulizer at this operating pressure is approximately 3 L/minute. Thegenerated aerosols are driven into the chambers by positive pressure. Nodilution air is used during the delivery of aerosolized solutions.During the 10 minute nebulization, approximately 1.8 mL of solution isnebulized. This is measured gravimetrically by comparing pre- andpost-nebulization weights of the filled nebulizer.

The bronchoprotective effects of test compounds administered viainhalation are evaluated using whole body plethysmography at 1.5, 24, 48and 72 hours post-dose. Forty-five minutes prior to the start of thepulmonary evaluation, each guinea pig is anesthetized with anintramuscular injection of ketamine (43.75 mg/kg), xylazine (3.50 mg/kg)and acepromazine (1.05 mg/kg). After the surgical site is shaved andcleaned with 70% alcohol, a 2-3 cm midline incision of the ventralaspect of the neck was made. Then, the jugular vein is isolated andcannulated with a saline-filled polyethylene catheter (PE-50, BectonDickinson, Sparks, Md.) to allow for intravenous infusions of ACh(Sigma-Aldrich, St. Louis, Mo.) in saline. The trachea is then dissectedfree and cannulated with a 14G teflon tube (#NE-014, Small Parts, MiamiLakes, Fla.). If required, anesthesia is maintained by additionalintramuscular injections of the aforementioned anesthetic mixture. Thedepth of anesthesia is monitored and adjusted if the animal responds topinching of its paw or if the respiration rate is greater than 100breaths/minute.

Once the cannulations are complete, the animal is placed into aplethysmograph (#PLY3114, Buxco Electronics, Inc., Sharon, Conn.) and anesophageal pressure cannula (PE-160, Becton Dickinson, Sparks, Md.) isinserted to measure pulmonary driving pressure (pressure). The teflontracheal tube is attached to the opening of the plethysmograph to allowthe guinea pig to breathe room air from outside the chamber. The chamberis then sealed. A heating lamp is used to maintain body temperature andthe guinea pig's lungs are inflated 3 times with 4 mL of air using a 10mL calibration syringe (#5520 Series, Hans Rudolph, Kansas City, Mo.) toensure that the lower airways do not collapse and that the animal doesnot suffer from hyperventilation. Once it is determined that baselinevalues are within the range 0.3-0.9 mL/cm H₂O for compliance and withinthe range 0.1-0.199 cm H₂O/mL per second for resistance, the pulmonaryevaluation is initiated. A Buxco pulmonary measurement computer programenables the collection and derivation of pulmonary values. Starting thisprogram initiates the experimental protocol and data collection. Thechanges in volume over time that occur within the plethysmograph witheach breath are measured via a Buxco pressure transducer. By integratingthis signal over time, a measurement of flow is calculated for eachbreath. This signal, together with the pulmonary driving pressurechanges, which are collected using a Sensym pressure transducer(#TRD4100), is connected via a Buxco (MAX 2270) preamplifier to a datacollection interface (#'s SFT3400 and SFT3813). All other pulmonaryparameters are derived from these two inputs.

Baseline values are collected for 5 minutes, after which time the guineapigs are challenged with ACh. ACh (0.1 mg/mL) is infused intravenouslyfor 1 minute from a syringe pump (sp210iw, World Precision Instruments,Inc., Sarasota, Fla.) at the following doses and prescribed times fromthe start of the experiment: 1.9 μg/minute at 5 minutes, 3.8 μg/minuteat 10 minutes, 7.5 μg/minute at 15 minutes, 15.0 μg/minute at 20minutes, 30 μg/minute at 25 minutes and 60 μg/minute at 30 minutes. Ifresistance or compliance has not returned to baseline values at 3minutes following each ACh dose, the guinea pig's lungs are inflated 3times with 4 mL of air from a 10 mL calibration syringe. Recordedpulmonary parameters includes respiration frequency (breaths/minute),compliance (mL/cm H₂O) and pulmonary resistance (cm H₂O/mL per second).Once the pulmonary function measurements are completed at minute 35 ofthis protocol, the guinea pig is removed from the plethysmograph andeuthanized by carbon dioxide asphyxiation.

The data are evaluated in one or both of the following ways:

(a) Pulmonary resistance (R_(L), cm H₂O/mL per second) is calculatedfrom the ratio of “change in pressure” to “the change in flow.” TheR_(L) response to ACh (60 μg/min, IH) is computed for the vehicle andthe test compound groups. The mean ACh response in vehicle-treatedanimals, at each pre-treatment time, is calculated and used to compute %inhibition of ACh response, at the corresponding pre-treatment time, ateach test compound dose. Inhibition dose-response curves for ‘R_(L)’ arefitted with a four parameter logistic equation using GraphPad Prism,version 3.00 for Windows (GraphPad Software, San Diego, Calif.) toestimate bronchoprotective ID₅₀ (dose required to inhibit the ACh (60μg/min) bronchoconstrictor response by 50%). The equation used is asfollows:Y=Min+(Max−Min)/(1+10^(((log ID50−X)*Hillslope)))where X is the logarithm of dose, Y is the response (% Inhibition of AChinduced increase in R_(L)). Y starts at Min and approachesasymptotically to Max with a sigmoidal shape.

(b) The quantity PD₂, which is defined as the amount of ACh or histamineneeded to cause a doubling of the baseline pulmonary resistance, iscalculated using the pulmonary resistance values derived from the flowand the pressure over a range of ACh or histamine challenges using thefollowing equation (which is derived from a equation used to calculatePC₂₀ values described in American Thoracic Society. Guidelines formethacholine and exercise challenge testing—1999. Am J Respir Crit CareMed. 161: 309-329 (2000)):

${PD}_{2} = {{antilog}\left\lbrack {{\log\mspace{11mu} C_{1}} + \frac{\left( {{\log\mspace{11mu} C_{2}} - {\log\mspace{11mu} C_{1}}} \right)\left( {{2R_{0}} - R_{1}} \right)}{R_{2} - R_{1}}} \right\rbrack}$where: C₁ is the concentration of ACh or histamine preceding C₂; C₂ isthe concentration of ACh or histamine resulting in at least a 2-foldincrease in pulmonary resistance (R_(L)); R₀ is the baseline R_(L)value; R₁ is the R_(L) value after C₁; and R₂ is the R_(L) value afterC₂. An efficacious dose is defined as a dose that limits thebronchrestriction response to a 50 μg/mL dose of ACh to a doubling ofthe baseline pulmonary resistance (PD₂₍₅₀₎).

Statistical analysis of the data is performed using a two-tailedStudents t-test. A P-value <0.05 is considered significant. Generally,test compounds having a PD₂₍₅₀₎ less than about 200 μg/mL forACh-induced bronchoconstriction at 1.5 hours post-dose in this assay arepreferred. Compounds of the invention are expected to have a PD₂₍₅₀₎ ofless than about 200 μg/mL for ACh-induced bronchoconstriction at 1.5hours post-dose, when tested in this or a similar assay.

Assay 4 Inhalation Guinea Pig Salivation Assay

Guinea pigs (Charles River, Wilmington, Mass.) weighing 200-350 g areacclimated to the in-house guinea pig colony for at least 3 daysfollowing arrival. Test compound or vehicle are dosed via inhalation(IH) over a 10 minute time period in a pie shaped dosing chamber (R&SMolds, San Carlos, Calif.). Test solutions are dissolved in sterilewater and delivered using a nebulizer filled with 5.0 mL of dosingsolution. Guinea pigs are restrained in the inhalation chamber for 30minutes. During this time, guinea pigs are restricted to an area ofapproximately 110 sq. cm. This space is adequate for the animals to turnfreely, reposition themselves, and allow for grooming. Following 20minutes of acclimation, guinea pigs are exposed to an aerosol generatedfrom a LS Star Nebulizer Set (Model 22F51, PARI Respiratory Equipment,Inc. Midlothian, Va.) driven by house air at a pressure of 22 psi. Uponcompletion of nebulization, guinea pigs are evaluated at 1.5, 6, 12, 24,48, or 72 hrs after treatment.

Guinea pigs are anesthetized one hour before testing with anintramuscular (IM) injection of a mixture of ketamine 43.75 mg/kg,xylazine 3.5 mg/kg, and acepromazine 1.05 mg/kg at an 0.88 mL/kg volume.Animals are placed ventral side up on a heated (37° C.) blanket at a 20degree incline with their head in a downward slope. A 4-ply 2×2 inchgauze pad (Nu-Gauze General-use sponges, Johnson and Johnson, Arlington,Tex.) is inserted in the guinea pig's mouth. Five minutes later, themuscarinic agonist pilocarpine (3.0 mg/kg, SC) is administered and thegauze pad is immediately discarded and replaced by a new pre-weighedgauze pad. Saliva is collected for 10 minutes, at which point the gauzepad is weighed and the difference in weight recorded to determine theamount of accumulated saliva (in mg). The mean amount of salivacollected for animals receiving the vehicle and each dose of testcompound is calculated. The vehicle group mean is considered to be 100%salivation. Results are calculated using result means (n=3 or greater).Confidence intervals (95%) are calculated for each dose at each timepoint using two-way ANOVA. This model is a modified version of theprocedure described in Rechter, “Estimation of anticholinergic drugeffects in mice by antagonism against pilocarpine-induced salivation”Ata Pharmacol Toxicol 24:243-254 (1996).

The mean weight of saliva in vehicle-treated animals, at eachpre-treatment time, is calculated and used to compute % inhibition ofsalivation, at the corresponding pre-treatment time, at each dose. Theinhibition dose-response data are fitted to a four parameter logisticequation using GraphPad Prism, version 3.00 for Windows (GraphPadSoftware, San Diego, Calif.) to estimate anti-sialagogue ID₅₀ (doserequired to inhibit 50% of pilocarpine-evoked salivation). The followingequation is used:Y=Min+(Max−Min)/(1+10^(((log ID50−X)*Hillslope)))where X is the logarithm of dose, Y is the response (% inhibition ofsalivation). Y starts at Min and approaches asymptotically to Max with asigmoidal shape. The ratio of the anti-sialagogue ID₅₀ tobronchoprotective ID₅₀ is used to compute the apparent lung-selectivityindex of the test compound. Generally, compounds having an apparentlung-selectivity index greater than about 5 are preferred. Compounds ofthe invention are expected to have an apparent lung-selectivity indexgreater than 5, when tested in this or a similar assay.

Assay 5 Methacholine-Induced Depressor Responses in Conscious GuineaPigs

Healthy, adult, male Sprague-Dawley guinea pigs (Harlan, Indianapolis,Ind.), weighing between 200 and 300 g are used in these studies. Underisoflurane anesthesia (to effect), animals are instrumented with commoncarotid artery and jugular vein catheters (PE-50 tubing). The cathetersare exteriorized utilizing a subcutaneous tunnel to the subscapulararea. All surgical incisions are sutured with 4-0 Ethicon Silk and thecatheters locked with heparin (1000 units/mL). Each animal isadministered saline (3 mL, SC) at the end of surgery as well asbuprenorphine (0.05 mg/kg, IM). Animals are allowed to recover on aheating pad before being returned to their holding rooms. Approximately18 to 20 hours following surgery, the animals are weighed and thecarotid artery catheter on each animal is connected to a transducer forrecording arterial pressure. Arterial pressure and heart rate arerecorded using a Biopac MP-100 Acquisition System. Animals are allowedto acclimate and stabilize for a period of 20 minutes.

Each animal is challenged with MCh (0.3 mg/kg, IV) administered throughthe jugular venous line and the cardiovascular response is monitored for10 minutes. The animals are then placed into the whole body dosingchamber, which is connected to a nebulizer containing the test compoundor vehicle solution. The solution is nebulized for 10 minutes using agas mixture of breathable air and 5% carbon dioxide with a flow rate of3 liters/minute. The animals are then removed from the whole bodychamber and returned to their respective cages. At 1.5 and 24 hourspost-dosing, the animals are re-challenged with MCh (0.3 mg/kg, IV) andthe hemodynamic response is determined. Thereafter, the animals areeuthanized with sodium pentobarbital (150 mg/kg, IV). MCh produces adecrease in mean arterial pressure (MAP) and decrease in heart rate(bradycardia). The peak decrease, from baseline, in MAP (depressorresponses) is measured for each MCh challenge (before and after IHdosing). The effects of treatment on the MCh responses are expressed as% inhibition (mean+/−SEM) of the control depressor responses. Two-wayANOVA with the appropriate post-hoc test is used to test the effects oftreatment and pre-treatment time. The depressor responses to MCh areexpected to be relatively unchanged at 1.5 and 24 hours after inhalationdosing with vehicle. The ratio of the anti-depressor ID₅₀ tobronchoprotective ID₅₀ is used to compute apparent lung-selectivity ofthe test compound. Generally, compounds having an apparentlung-selectivity index greater than 5 are preferred. It is expected thatthe compounds of the invention will exhibit an apparent lung-selectivityindex greater than 5, as measured in this or a similar assay.

While the present invention has been described with reference tospecific aspects or embodiments thereof, it will be understood by thoseof ordinary skilled in the art that various changes can be made orequivalents can be substituted without departing from the true spiritand scope of the invention. Additionally, to the extent permitted byapplicable patent statues and regulations, all publications, patents andpatent applications cited herein are hereby incorporated by reference intheir entirety to the same extent as if each document had beenindividually incorporated by reference herein.

1. A compound of formula I:

wherein: a is 0 or an integer of from 1 to 5; each R¹ is independently selected from —C₁₋₅alkyl, —C₂₋₅alkenyl, —C₂₋₅alkynyl, —C₃₋₆cycloalkyl, -cyano, -halo, —OR^(1a), —C(O)OR^(1b), —SR^(1c), —S(O)R^(1d), —S(O)₂R^(1e), —NR^(1f)R^(1g), —NR^(1h)S(O)₂R^(1i), and —NR^(1j)C(O)R^(1k); where each of R^(1a-1k) is independently —H, —C₁₋₅alkyl or phenyl-C₁₋₅alkyl; b is 0 or an integer of from 1 to 4; each R² is independently selected from —C₁₋₅alkyl, —C₂₋₅alkenyl, —C₂₋₅alkynyl, —C₃₋₆cycloalkyl, -cyano, -halo, —OR^(2a), —C(O)OR^(2b), —SR^(2c), —S(O)R^(2d), —S(O)₂R^(2e), —NR^(2f)R^(2g), —NR^(2h)S(O)₂R^(2i), and —NR^(2j)C(O)R^(2k); where each of R^(2a-2k) is independently —H, —C₁₋₅alkyl or -phenyl-C₁₋₅alkyl; W is —O— or —NW^(a)—, where W^(a) is —H or —C₁₋₅alkyl; c is 0 or an integer from 1 to 5; each R³ independently is —C₁₋₅alkyl or two R³ groups are joined to form C₁₋₃alkylene, C₂₋₃alkenylene or oxiran-2,3-diyl; m is 0 or 1; Z is selected from —C(O)N(R⁴)— and —N(R⁴)C(O)—, where R⁴ is selected from —H, —C₁₋₅alkyl, and —C₃₋₅cycloalkyl; s is 0, 1 or 2; Ar is a phenylene substituted with (R⁵)_(q) where q is 0 or an integer from 1 to 4 and each R⁵ is independently selected from -halo, —OH, —C₁₋₅alkyl, and —C₁₋₅alkoxy; t is 0, 1 or 2; R⁶ is selected from —H, —C₁₋₅alkyl, and —X⁶R^(6a); where X⁶ is —C₁₋₅alkylene and R^(6a) is selected from —OH, —C₁₋₅alkoxy and -heteroaryl; and R⁷ is selected from —H, —C₁₋₅alkyl, —C₃₋₆cycloalkyl, and —X⁷R^(7a); where X⁷ is selected from —C₁₋₅alkylene, —C(O)—, —C₁₋₅alkylene-C(O)—, —S(O₂)—, —C₁₋₅alkylene-S(O₂)—, and —S(O₂)—C₁₋₅alkylene; and R^(7a) is selected from —OH, —C₁₋₅alkyl, —C₃₋₆cycloalkyl, —C₁₋₅alkoxy, heteroaryl, —NR^(7b)R^(7c), where R^(7b) and R^(7c) are independently —H or —C₁₋₅alkyl wherein each alkyl and alkoxy group in R¹, R^(1a-1k), R², R^(2a-2k), R³, R⁵, R⁶, R⁷, and R^(7a-c) is optionally substituted with 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or stereoisomer thereof.
 2. The compound of claim 1, wherein a, b and c each represent
 0. 3. The compound of claim 1, wherein W is —O—.
 4. The compound of claim 1, wherein m is 0 and t is
 1. 5. The compound of claim 1, wherein Z is selected from —NHC(O)—, —N(CH₃)C(O)—, and —C(O)NH—.
 6. The compound of claim 1, wherein Ar is selected from phenylene and phenylene substituted with methoxy.
 7. The compound of claim 6, wherein Ar is selected from phen-1,3-ylene, phen-1,4-ylene, and 2-methoxyphen-1,4-ylene.
 8. The compound of claim 3, wherein m is 0 and t is
 1. 9. The compound of claim 8, wherein a, b, and c are 0; Z is selected from —NHC(O)—, —N(CH₃)C(O)—, and —C(O)NH—; and Ar is selected from phenylene and phenylene substituted with methoxy.
 10. The compound of claim 1, wherein R⁶ is —H and R⁷ is selected from —H, —C₁₋₅alkyl, —C₃₋₆cycloalkyl, —C₁₋₅alkylene-OH, —C₁₋₅alkylene-C₃₋₆cycloalkyl, —C₁₋₅alkylene-C₁₋₅alkoxy, —C₁₋₅alkyleneheteroaryl, —C(O)—C₁₋₅alkyl, —C(O)—C₃₋₆cycloalkyl, —C(O)-heteroaryl, —C₁₋₅alkylene-C(O)—NR^(7b)R^(7c), —S(O₂)—C₁₋₅alkyl, —S(O₂)-heteroaryl, —S(O₂)-aryl, and —S(O₂)—C₁₋₅alkylene-NR^(7b)R^(7c); where the aryl is optionally substituted with 1-2-C₁₋₅alkyl or halo groups, and wherein each alkyl and alkoxy group in R⁷ and R^(7b-c) is optionally substituted with 1 to 5 fluoro substituents.
 11. The compound of claim 1, wherein R⁶ is —C₁₋₅alkyl and R⁷ is selected from —C₁₋₅alkylene-OH, —C₁₋₅alkyleneheteroaryl, —C₁₋₅alkylene-C(O)OH, and —C₁₋₅alkylene-S(O₂)—C₁₋₅alkyl; and wherein each alkyl group in R⁷ is optionally substituted with 1 to 5 fluoro substituents.
 12. The compound of claim 1, wherein R⁶ and R⁷ are different —C₁₋₅alkyl groups.
 13. The compound of claim 1, wherein R⁶ and R⁷ are the same, and are selected from: —C₁₋₅alkyl, —C₁₋₅alkylene-OH, and —C₁₋₅alkylene-C₁₋₅alkoxy.
 14. The compound of claim 1, selected from: biphenyl-2-ylcarbamic acid 1-{2-[(4-aminomethylbenzoyl)methylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(furan-2-carbonyl)amino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(acetylaminomethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[methyl-(4-{[(pyridine-4-carbonyl)amino]methyl}benzoyl)amino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(cyclopropanecarbonylamino)methyl]benzoyl]methylamino)ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[methyl-(4-{[(thiophene-2-carbonyl)amino]methyl}benzoyl)amino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(cyclobutanecarbonylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(isopropylaminomethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(cyclopropylmethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(2-methanesulfonylethyl)methylamino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(ethylisopropylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-{[bis-(2-hydroxyethyl)amino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(tert-butylaminomethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(ethylmethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-{[bis-(2-ethoxyethyl)amino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(methyl-{4-[(methylpyridin-3-ylmethylamino) methyl]benzoyl}amino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-{[bis(2-methoxyethyl)amino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-{[(2-hydroxyethyl)methylamino]methyl}benzoyl)methylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(methyl-{4-[(methyl-pyridin-4-ylmethylamino) methyl]benzoyl}amino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(2-hydroxyethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(2-hydroxyethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-ethylaminomethylbenzoyl)methylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(4-cyclopropylaminomethylbenzoyl)methylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(2-methoxyethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(carbamoylmethylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-aminomethylbenzoylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-aminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-{[(pyridin-4-ylmethyl)amino]methyl}benzylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{3-[(furan-2-ylmethylmethylamino)methyl]benzylcarbamoyl}ethyl)piperidin-4-yl ester; {[3-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionylamino}methyl)benzyl]methylamino}acetic acid; biphenyl-2-ylcarbamic acid 1-[2-(3-cyclobutylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-cyclopropylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-methylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-dimethylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{methyl-[3-(4-methylaminomethylphenyl)propionyl]amino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[3-(4-ethylaminomethylphenyl)propionyl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-aminomethylphenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(4-trifluoromethylbenzenesulfonylamino) methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(butane-1-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(2-fluorobenzenesulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(quinoline-8-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(ethanesulfonylaminomethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(2,6-dichlorobenzenesulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(toluene-4-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(thiophene-2-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(benzenesulfonylaminomethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(methanesulfonylaminomethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(trifluoromethanesulfonylaminomethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(propane-1-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(propane-2-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(pyridin-2-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(pyridin-3-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(pyridin-4-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(benzo[1,3]dioxol-5-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(1H-indol-7-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(isobutylaminomethyl)phenylcarbamoyl]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(4-{[(thiophen-2-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(3,3,3-trifluoropropylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{4-[(2-methylaminoethanesulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[3-(4-methylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[3-(4-ethylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{3-[4-(isopropylaminomethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[3-(4-cyclopropylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(cyclopropylmethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[3-(4-cyclopentylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(2-hydroxyethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(2-methoxyethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(carbamoylmethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{[bis-(2-hydroxyethyl)amino]methyl}phenyl)propionylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[2-(4-methylaminomethylphenyl)acetylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[2-(4-ethylaminomethylphenyl)acetylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2-{4-[(2-hydroxyethylamino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2-{4-[(2-methoxyethylamino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2-{4-[(carbamoylmethylamino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[(2-methoxy-4-methylaminomethylbenzoyl)methylamino]ethyl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-({4-[(2-hydroxyethylamino)methyl]-2-methoxybenzoyl}methylamino)ethyl]piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-[2-(2-methoxy-4-methylaminomethylbenzoylamino) ethyl]piperidin-4-yl ester; and biphenyl-2-ylcarbamic acid 1-(2-{4-[(2-hydroxyethylamino)methyl]-2-methoxybenzoylamino}ethyl)piperidin-4-yl ester; or a pharmaceutically acceptable salt thereof.
 15. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim
 1. 16. The compound of claim 1 prepared by the process comprising: (a) reacting a compound of formula II:

 or a salt thereof, with a compound of formula III:

 wherein L¹ represents a leaving group; or (b) coupling a compound of formula IVa:

 or a reactive derivative thereof, with a compound of formula Va:

 or coupling a compound of formula IVb:

 with a compound of formula Vb:

 or a reactive derivative thereof; or (c) reacting a compound of formula VI:

 wherein L² represents a leaving group, with a compound of formula VII:

 or (d) reacting a compound of formula II with a compound of formula VIII:

 in the presence of a reducing agent; or (e) reacting a compound of formula IX:

 with a compound of formula VII in the presence of a reducing agent; and then (f) removing any protecting groups that may be present to provide a compound of formula I.
 17. The compound of claim 16, prepared by the process which further comprises forming a pharmaceutically acceptable salt of the compound of formula I. 